CN1972959A - Transferin derivatives and uses thereof - Google Patents

Abstract

The present invention provides stable transferin derivatives with excellent biological activities (such as anti-cancer metastasis and anti-cancer growth activities). By modifying the amino acids that make up transferin with specific modifying groups, these transferin derivatives exhibit superior blood stability compared to native transferin and also demonstrate excellent anti-cancer metastasis and anti-cancer growth activities. Furthermore, these transferin derivatives have been found to inhibit gonadotropin secretion and sex hormone secretion, activities that are completely different from previously known activities.

Description

Transferin derivatives and uses thereof

technical field

The present invention relates to metastin derivatives and uses thereof.

Background technique

Transferins of human origin (also known as KiSS-I peptides) (WO 00/24890) and transferins of rat or mouse origin (WO 01/75104) are known. Sustained release formulations containing transferins are also known (WO02/85399).

According to reports, metastasin has the effect of inhibiting cancer metastasis, so it is useful for the prevention or treatment of cancer (for example, lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer) cancer, kidney cancer, bladder cancer, brain tumors, etc.); transferin also has the effect of controlling the function of the pancreas, so it is effective for the prevention or treatment of pancreatic diseases (such as acute or chronic pancreatitis, pancreatic cancer, etc.); in addition, Transferin also has the effect of controlling placental function, so for the prevention or treatment of choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or abnormal delivery (WO 00/24890; WO 00/24890; 01/75104; WO02/85399) are valid.

Contents of the invention

The object of the present invention is to provide stable metastasin derivatives with excellent biological activity (cancer metastasis inhibitory activity, cancer growth inhibitory activity, etc.).

The inventors of the present invention conducted extensive studies to solve the above-mentioned problems, and unexpectedly found that by modifying the amino acids constituting transferin with a specific modifying group, transferin derivatives exhibit superior stability in blood, etc., compared to natural transferin, and also exhibit Excellent anti-cancer metastasis activity or anti-cancer growth activity. The present inventors also unexpectedly found that these transferin derivatives have the effect of inhibiting the secretion of gonadotropin, the effect of inhibiting the secretion of sex hormones, etc., and these effects are completely different from the previously known effects. The present inventors completed the present invention through further studies based on these findings.

The present invention provides the following features and the like.

(1) A transferin derivative (II) represented by the following formula, or a salt thereof,

[Wherein, V represents the group shown in the following formula:

Or a group represented by the following formula:

n means 0 or 1;

W ¹ represents N, CH or O (provided that when W ¹ is N or CH, n represents 1, and when W ¹ is O, n represents 0);

W ² represents N or CH;

Z ¹ , Z ³ , Z ⁵ and Z ⁷ represent a hydrogen atom or a C _1-3 alkyl group;

Z ⁴ , Z ⁶ and Z ⁸ represent a hydrogen atom, O or S, respectively;

R ² represents (1) a hydrogen atom, or (2) a cyclic or chain (linear) C _1-10 alkyl group, or (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a chained alkyl group , or (4) C _1-8 alkyl, said C _1-8 alkyl is optionally substituted by a substituent selected from an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic ring group replace;

^R represents (1) C _1-8 alkyl, said C _1-8 alkyl has an optionally substituted basic group and optionally has other substituents, (2) aralkyl, said aralkyl An optionally substituted basic group and optionally other substituents, (3) C _1-4 alkyl, the C _1-4 alkyl having a non-aromatic ring hydrocarbon group with no more than 7 carbon atoms and any Optionally have other substituents, the non-aromatic cyclic hydrocarbon group has an optionally substituted basic group, or (4) C _1-4 alkyl, the C _1-4 alkyl has no more than 7 carbon atoms A non-aromatic heterocyclic group and optionally other substituents, the non-aromatic heterocyclic group has an optionally substituted basic group;

R ⁴ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally Substituted C ^8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms , the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms Aromatic heterocyclic group;

Q ¹ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally Substituted C _8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms , the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms Aromatic heterocyclic group;

Q ² represents (1) CH ₂ , which may _{be optionally substituted by optionally substituted C 1-4 alkyl} having a substituent selected from carbamoyl _and hydroxyl, ( 2) NH, which _may be optionally substituted by optionally substituted C _1-4 alkyl having a substituent selected from carbamoyl and hydroxyl, or (3) O;

Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH ₂ - or -CH=CH-, which may be optionally substituted by C _1-6 alkyl; and,

Z ⁹ represents a hydrogen atom, O or S; and,

P and P' can be the same or different, and each can form a ring through the combination of P and P', or P and ^Q1 , representing:

(1) Hydrogen atom;

(2) Optional amino acid residues that are continuously or discontinuously combined with the C-terminus of the 1-48 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1;

(3) A group represented by the following formula:

J ¹ -J ² -C(J ³ )(Q ³ )Y ¹ C(J ⁴ )(Q ⁴ )y ² C(J ⁵ )(Q ⁵ )Y ³ C(J ⁶ )(Q ⁶ )C( =Z ¹⁰ )-(wherein,

^J represents (a) a hydrogen atom, or (b) (i) C _1-15 acyl, (ii) C _1-15 alkyl, (iii) C _6-14 aryl, (iv) carbamoyl, ( v) carboxy, (vi) sulfinate, (vii) amidino, (viii) glyoxyl or (ix) amino, these groups may be optionally substituted with substituents containing optionally substituted cyclic groups;

J ² represents (1) NH optionally substituted by C _1-6 alkyl, (2) CH ₂ optionally substituted by C _1-6 alkyl, (3) O, or (4) S;

Each of J ³ to J ⁶ represents a hydrogen atom or a C _1-3 alkyl group;

Q ³ to Q ⁶ each represent a C _1-4 alkyl group or a hydrogen atom, and the C _1-4 alkyl group optionally has a substituent selected from the following:

(1) Optionally substituted C _6-12 aromatic hydrocarbon groups,

(2) An optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atoms,

(3) Optionally substituted C ^8-14 aromatic condensed ring groups,

(4) An optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atom,

(5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms,

(6) An optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms,

(7) Optionally substituted amino groups,

(8) Optionally substituted guanidino,

(9) optionally substituted hydroxyl,

(10) Optionally substituted carboxy,

(11) optionally substituted carbamoyl, and

(12) optionally substituted mercapto;

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ can be combined together, or J ² and Q ³ , Y ¹ and Q 4 , Y ² and Q ⁵ or Y ^{3 and} Q ⁶ can be combined to form a ring;

Each of ^Y1 to ^Y3 represents a group shown below:

-CON(J ¹³ )-, -CSN(J ¹³ )-, -C(J ¹⁴ )N(J ¹³ )-or -N(J ¹³ )CO- (wherein J ¹³ and J ¹⁴ each represent a hydrogen atom or C _1-3 alkyl); and

Z ¹⁰ represents a hydrogen atom, O or S);

(4) A group represented by the following formula:

J ¹ -J ² -C(J ⁷ )(Q ⁷ )Y ² C(J ⁸ )(Q ⁸ )Y ³ C(J ⁹ )(Q ⁹ )C(=Z ¹⁰ )-

(in:

^J1 and ^J2 each have the same meaning as above;

J ⁷ to J ⁹ have the same meaning as J ³ ;

Q ⁷ to Q ⁹ have the same meaning as Q ³ ;

^Y2 and ^Y3 each have the same meaning as above;

Z ¹⁰ has the same meaning as above;

J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ can be combined together, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ can be combined together to form a ring);

(5) A group represented by the following formula:

J ¹ -J ² -C(J ¹⁰ )(Q ¹⁰ )Y ³ C(J ¹¹ )(Q ¹¹ )C(=Z ¹⁰ )-

(in:

J ¹ and J ² have the same meaning as above;

J ¹⁰ and J ¹¹ have the same meaning as J ³ ;

Q ¹⁰ and Q ¹¹ have the same meaning as Q ³ ;

^Y3 has the same meaning as above;

Z ¹⁰ has the same meaning as above;

J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ can be combined together, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ can be combined to form a ring);

(6) A group represented by the following formula:

J ¹ -J ² -C(J ¹² )(Q ¹² )C(=Z ¹⁰ )-

(in:

J ¹ and J ² have the same meaning as above;

J ¹² has the same meaning as J ³ ;

Q ¹² has the same meaning as Q ³ ;

Z ¹⁰ has the same meaning as above;

J ¹² and Q ¹² may be combined together, or J ² and Q ¹² may be combined to form a ring); or,

(7) A group represented by the following formula:

J ¹ -

(in:

^J1 has the same meaning as above)] (the condition is to remove the sequence consisting of 1-54, 2-54, 3-54, 4-54, 5-54, 6-54, 7 in the amino acid sequence shown in SEQ ID NO: 1 -54, 8-54, 9-54, 10-54, 11-54, 12-54, 13-54, 14-54, 15-54, 16-54, 17-54, 18-54, 19-54 , 20-54, 21-54, 22-54, 23-54, 24-54, 25-54, 26-54, 27-54, 28-54, 29-54, 30-54, 31-54, 32 -54, 33-54, 34-54, 35-54, 36-54, 37-54, 38-54, 39-54, 40-54, 41-54, 42-54, 43-54, 44-54 , 45-54, 46-54, 47-54, 48-54 or 49-54 amino acid sequence group peptide).

(2) The transferin derivative (II) or a salt thereof according to (1), wherein V is a group represented by the following formula:

(Wherein, the meaning of each symbol is the same as in (1)).

(3) The transferin derivative (II) or a salt thereof according to (1), wherein V is a group represented by the following formula:

(wherein, each symbol is the same as the definition in (1)).

The present invention also provides the following features and the like.

(4) A prodrug of the transferin derivative (II) or a salt thereof as described in (1).

(5) A pharmaceutical composition (pharmaceutical), comprising the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof.

(6) The pharmaceutical composition according to (5), which is an agent for suppressing cancer metastasis or an agent for suppressing cancer growth.

(7) The pharmaceutical composition according to (5), which is a drug for preventing or treating cancer.

(8) The pharmaceutical composition as described in (5), which is a drug for controlling pancreatic function.

(9) The pharmaceutical composition as described in (5), which is a drug for preventing or treating acute or chronic pancreatitis or pancreatic cancer.

(10) The pharmaceutical composition according to (5), which is a drug for controlling placental function.

(11) The pharmaceutical composition as described in (5), which is used for the prevention or treatment of choriocarcinoma, mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism, and labor induction drug.

(12) The pharmaceutical composition as described in (5), which is a drug for improving gonadal function.

(13) The pharmaceutical composition according to (5), which is a drug for preventing or treating hormone-dependent cancer, infertility, endometriosis, premature puberty or uterine fibroids.

(14) The pharmaceutical composition as described in (5), which is a drug for inducing or stimulating ovulation.

(15) The pharmaceutical composition according to (5), which is a gonadotropin secretagogue or a sex hormone secretagogue.

(16) The pharmaceutical composition as described in (5), which is used for preventing or treating Alzheimer's disease or mild cognitive impairment.

(17) A method for inhibiting cancer metastasis or cancer growth, which comprises administering an effective dose of the transferin derivative (II) or a salt thereof according to (1), or a prodrug thereof, to a mammal.

(18) A method for preventing or treating cancer, which comprises administering an effective dose of the transferin derivative (II) or a salt thereof according to (1), or a prodrug thereof, to a mammal.

(19) A method for controlling pancreatic function, which comprises administering to a mammal an effective dose of the transferin derivative (II) as described in (1) or a salt thereof, or a prodrug thereof.

(20) A method for preventing or treating acute or chronic pancreatitis or pancreatic cancer, comprising administering an effective dose of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, to a mammal.

(21) A method for controlling placental function, which comprises administering an effective dose of the transferin derivative (II) or a salt thereof according to (1), or a prodrug thereof, to a mammal.

(22) A method for preventing or treating choriocarcinoma, hydatidiform mole, invasive hydatidiform mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction, which comprises administering an effective dose of such as (1) to mammals The transferin derivatives (II) or their salts, or their prodrugs.

(23) A method for improving gonadal function, which comprises administering an effective dose of the transferin derivative (II) or a salt thereof according to (1), or a prodrug thereof, to a mammal.

(24) A method for preventing or treating hormone-dependent cancer, infertility, endometriosis, premature puberty, or uterine fibroids, comprising administering an effective dose of the transferin derivative as described in (1) to a mammal ( II) or salts thereof, or their prodrugs.

(25) A method for inducing or stimulating ovulation, which comprises administering an effective dose of the transferin derivative (II) or a salt thereof according to (1), or a prodrug thereof, to a mammal.

(26) A method for promoting gonadotropin secretion or sex hormone secretion, which comprises administering an effective dose of the transferin derivative (II) or salt thereof according to (1) or a prodrug thereof to a mammal.

(27) A method for preventing or treating Alzheimer's disease or mild cognitive impairment, which comprises administering an effective dose of the transferin derivative (II) or a salt thereof as described in (1), or their prodrug.

(28) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the preparation of a medicament for inhibiting cancer metastasis or cancer growth.

(29) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the preparation of a medicament for preventing or treating cancer.

(30) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the preparation of a medicament for controlling pancreatic function.

(31) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the manufacture of a medicament for the prevention or treatment of acute or chronic pancreatitis or pancreatic cancer.

(32) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the manufacture of a medicament for controlling placental function.

(33) The transferin derivatives (II) or their salts as described in (1), or their prodrugs are used for the prevention or treatment of choriocarcinoma, hydatidiform mole, invasive hydatidiform mole, miscarriage, fetal hypoplasia , the use of a drug for abnormal glucose metabolism, abnormal lipid metabolism or labor induction.

(34) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the preparation of a medicament for improving gonadal function.

(35) The transferin derivatives (II) or salts thereof as described in (1), or their prodrugs are used for the prevention or treatment of hormone-dependent cancer, infertility, endometriosis, premature puberty or Use in medicine for uterine fibroids.

(36) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the manufacture of a medicament for inducing or stimulating ovulation.

(37) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the preparation of a gonadotropin secretagogue or a sex hormone secretagogue.

(38) Use of the transferin derivative (II) or a salt thereof as described in (1), or their prodrugs in the preparation of a medicament for preventing or treating Alzheimer's disease or mild cognitive impairment use.

(39) A glucagon secretagogue comprising the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof.

(40) A drug for promoting urine production, comprising the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof.

(41) For the prevention or treatment of obesity, hyperlipidemia, type II diabetes, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, dysuria, insulin resistance, instability Drugs for chronic diabetes, lipoatrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disease or lipotoxicity, which include transferin derivatives (II) or salts thereof as described in (1), or their prodrug.

(42) A method for promoting glucagon secretion, which comprises administering to a mammal an effective dose of the transferin derivative (II) or a salt thereof according to (1), or a prodrug thereof.

(43) A method for promoting urine production, comprising administering to a mammal an effective dose of the transferin derivative (II) or a salt thereof according to (1), or a prodrug thereof.

(44) Prevention or treatment of obesity, hyperlipidemia, type II diabetes, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, dysuria, insulin resistance, unstable diabetes, A method for lipoatrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disease, or lipotoxicity, comprising administering an effective dose of the transferin derivative (II) or a salt thereof as described in (1) to a mammal , or their prodrugs.

(45) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, in the preparation of a glucagon secretagogue.

(46) Use of the transferin derivative (II) or a salt thereof as described in (1), or a prodrug thereof, for the manufacture of a medicament for promoting urine production.

(47) The transferin derivatives (II) or salts thereof as described in (1), or their prodrugs are used for the prevention or treatment of obesity, hyperlipidemia, type II diabetes, hypoglycemia, hypertension, Drugs for diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, dysuria, insulin resistance, unstable diabetes, lipoatrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disease, or lipotoxicity the use of.

(48) A drug for inhibiting the secretion of gonadotropins or a drug for inhibiting the secretion of sex hormones, which includes a transferin derivative (III) or a salt thereof represented by the following formula, or a prodrug thereof,

[in:

V' represents a group shown in the following formula:

Or a group represented by the following formula:

Or a group represented by the following formula:

n means 0 or 1;

W ¹ represents N, CH or O (provided that when W ¹ is N or CH, n represents 1, and when W ¹ is O, n represents 0);

W ² represents N or CH;

Z ¹ , Z ³ , Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group;

Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S;

^R represents (1) a hydrogen atom, (2) a C _1-8 alkyl group, and the C _1-8 alkyl group is optionally selected from optionally substituted carbamoyl, optionally substituted hydroxyl and optionally Substituent substituents of substituted aromatic ring groups, (3) cyclic or chain C _1-10 alkyl, or (4) C _1-10 alkyl consisting of cycloalkyl and chain alkyl, or (5) Optionally substituted aromatic ring groups;

R ² represents (1) hydrogen atom, or (2) cyclic or chain C _1-10 alkyl, (3) C _1-10 alkyl consisting of cycloalkyl and chain alkyl, or (4) C _1-8 alkyl, the C _1-8 alkyl is optionally substituted by a substituent selected from an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic ring group;

^R represents (1) C _1-8 alkyl, said C _1-8 alkyl has an optionally substituted basic group and optionally has other substituents, (2) aralkyl, said aralkyl An optionally substituted basic group and optionally other substituents, (3) C _1-4 alkyl, the C _1-4 alkyl having a non-aromatic ring hydrocarbon group with no more than 7 carbon atoms and any Optionally have other substituents, the non-aromatic cyclic hydrocarbon group has an optionally substituted basic group, or (4) C _1-4 alkyl, the C _1-4 alkyl has no more than 7 carbon atoms A non-aromatic heterocyclic group and optionally other substituents, the non-aromatic heterocyclic group has an optionally substituted basic group;

R ⁴ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally substituted C _8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms, the hetero Atoms selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic heterocyclic rings with no more than 7 carbon atoms base;

Q ¹ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally substituted C _8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms, the hetero Atoms selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic heterocyclic rings with no more than 7 carbon atoms base;

Q ² represents (1) CH ₂ , which may _{be optionally substituted by optionally substituted C 1-4 alkyl} having a substituent selected from carbamoyl _and hydroxyl, ( ₂ ) NH, which may be optionally substituted by optionally substituted C _1-4 alkyl having a substituent selected from carbamoyl and hydroxy, or (3) O; Y Indicates groups represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH ₂ -, -CH=CH-, which may be optionally substituted by C _1-6 alkyl; and,

Z ⁹ represents a hydrogen atom, O or S; and,

P and P' can be the same or different, and each can form a ring together through the combination of P and P' or P and ^Q1 , representing:

(1) Hydrogen atom;

(2) Optional amino acid residues that are continuously or discontinuously combined with the C-terminus of the 1-48 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1;

(3) A group represented by the following formula:

J ¹ -J ² -C(J ³ )(Q ³ )Y ¹ C(J ⁴ )(Q ⁴ )Y ² C(J ⁵ )(Q ⁵ )Y ³ C(J ⁶ )(Q ⁶ )C( =Z ¹⁰ )-

(in:

^J represents (a) a hydrogen atom, or (b) (i) C _1-15 acyl, (ii) C _1-15 alkyl, (iii) C _6-14 aryl, (iv) carbamoyl, ( v) carboxy, (vi) sulfinate, (vii) amidino, (viii) glyoxyl or (ix) amino, these groups may be optionally substituted with substituents containing optionally substituted cyclic groups;

J ² represents (1) NH optionally substituted by C _1-6 alkyl, (2) CH ₂ optionally substituted by C _1-6 alkyl, (3) O or (4) S;

Each of J ³ to J ⁶ represents a hydrogen atom or a C _1-3 alkyl group;

Q ³ to Q ⁶ each represent a C _1-4 alkyl group or a hydrogen atom, and the C _1-4 alkyl group optionally has a substituent selected from the following:

(1) Optionally substituted C _6-12 aromatic hydrocarbon groups,

(2) An optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atoms,

(3) Optionally substituted C _8-14 aromatic condensed ring groups,

(4) An optionally substituted 5- to 14-membered aromatic condensed heterocyclic group consisting of 3 to 11 carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur atoms,

(5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms,

(6) An optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms,

(7) Optionally substituted amino groups,

(8) Optionally substituted guanidino,

(9) optionally substituted hydroxyl,

(10) Optionally substituted carboxy,

(11) optionally substituted carbamoyl, and

(12) optionally substituted mercapto;

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ can be combined together, or Z ¹ and R ¹ , J ² and Q 3 , Y ¹ and Q ⁴ , Y ^{2 and} Q ⁵ or Y ³ and Q ⁶ can be combined to form a ring;

Y ¹ to Y ³ each represent a group described in the following formula:

-CON(J ¹³ )-, -CSN(J ¹³ )-, -C(J ¹⁴ )N(J ¹³ )- or -N(J ¹³ )CO- (wherein J ¹³ and J ¹⁴ each represent a hydrogen atom or C _1-3 alkyl);

Z ¹⁰ represents a hydrogen atom, O or S);

(4) A group represented by the following formula:

J ¹ -J ² -C(J ⁷ )(Q ⁷ )Y ² C(J ⁸ )(Q ⁸ )Y ³ C(J ⁹ )(Q ⁹ )C(=Z ¹⁰ )-

(in:

^J1 and ^J2 each have the same meaning as above;

J ⁷ to J ⁹ have the same meaning as J ³ ;

Q ⁷ to Q ⁹ have the same meaning as Q ³ ;

^Y2 and ^Y3 each have the same meaning as above;

Z ¹⁰ has the same meaning as above;

J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ can be combined together, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ can be combined to form a ring);

(5) A group represented by the following formula:

J ¹ -J ² -C(J ¹⁰ )(Q ¹⁰ )Y ³ C(J ¹¹ )(Q ¹¹ )C(=Z ¹⁰ )-

(in:

J ¹ and J ² have the same meaning as above;

J ¹⁰ and J ¹¹ have the same meaning as J ³ ;

Q ¹⁰ and Q ¹¹ have the same meaning as Q ³ ;

^Y3 has the same meaning as above;

Z ¹⁰ has the same meaning as above;

J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ can be combined together, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ can be combined to form a ring);

(6) A group represented by the following formula:

J ¹ -J ² -C(J ¹² )(Q ¹² )C(=Z ¹⁰ )-

(in;

J ¹ and J ² have the same meaning as above;

J ¹² has the same meaning as J ³ ;

Q ¹² has the same meaning as Q ³ ;

Z ¹⁰ has the same meaning as above;

J ¹² and Q ¹² can be combined together, or J ² and Q ¹² can be combined together to form a ring);

or,

(7) A group represented by the following formula:

J ¹ - (wherein, J ¹ has the same meaning as above)]

(49) The drug as described in (48), wherein the transferin derivative (III) is the transferin derivative (II) as described in (1).

(50) The drug as described in (48), wherein V' is a group represented by the following formula:

(wherein each symbol has the same meaning as described in (48)).

(51) The drug as described in (48), wherein V' is a group represented by the following formula:

(wherein each symbol has the same meaning as described in (48)).

(52) The drug as described in (48), wherein V' is a group represented by the following formula:

(wherein each symbol has the same meaning as described in (48)).

(53) The drug according to (48), wherein the transferin derivative (III) is:

(1) D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 141),

(2) D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 174),

(3) 3-(3-indolyl)propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 260),

(4) 3-phenylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 269),

(5) 2-(Indol-3-yl)ethylcarbamoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 279),

(6) D-Tyr-Asn-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 286),

(7) D-Tyr-Asn-Trp-Asn-Ser-PheΨ(CSNH)Gly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 296),

(8) TyrΨ(CH ₂ NH)Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (compound number 300),

(9) D-Tyr-D-Asn-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 303),

(10) D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 305),

(11) D-Tyr-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂ (Compound No. 318),

(12) D-TYr-Asn-Trp-Asn-Ser-PheΨ(NHCO)Gly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 319),

(13) 3-(3-pyridyl)propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (compound number 322),

(14) 4-imidazole acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (compound number 323),

(15) GuAmb-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 332),

(16) GuAmb-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 333),

(17) GuAmb-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 334),

(18) 3-(3-indolyl)propionyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 339),

(19) Benzoyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 341),

(20) Indole-3-acetyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 345),

(21) Ac-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 346),

(22) Benzoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 353),

(23) 3-(3-indolyl) propionyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 354),

(24) Ac-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 358),

(25) 2-(indol-3-yl)ethylcarbamoyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 364),

(26) 2-(Indol-3-yl)ethylcarbamoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 369),

(27) (2S)-2-acethoxy-3-phenylpropionyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 373),

(28) (2S)-2-(3-indolylpropionyl)-3-phenylpropionyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 379),

(29) (2S)-2-benzoyl-3-phenylpropionyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 380),

(30) D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 385),

(31) 3-(3-pyridyl) propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (compound number 386),

(32) Dibenzylcarbamoyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 393),

(33) Benzylphenethylcarbamoyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 417),

(34) Benzoyl-PheΨ(NHCO)Gly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 423),

(35) Benzoyl-AzaPhe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 431),

(36) 3-pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (compound number 432),

(37) 2-pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 435),

(38) 4-pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 436),

(39) Propionyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 437),

(40) Isobutyryl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 438),

(41) Cyclohexanecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 439),

(42) Phenylacetyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 440),

(43) Benzoyl-Pya(2)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 441),

(44) 6-Methylnicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 445),

(45) pyrazine carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 446),

(46) Cyclopropanecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 447),

(47) Trifluoroacetyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 448),

(48) Benzoyl-Cha-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 449),

(49) Cyclopropanecarbonyl-Cha-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 451),

(50) (R)-3-Hydroxy-2-methylpropionyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 452),

(51) 2-Hydroxyisobutyryl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 453),

(52) 3-furyl carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 454),

(53) pyrrole-2-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 455),

(54) 4-imidazolecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 459),

(55) 6-Hydroxynicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 462),

(56) 6-chloronicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 463),

(57) 6-(trifluoromethyl)nicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 464),

(58) Dimethylcarbamoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 467),

(59) 1-azetidine carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (compound number 468),

(60) 4-pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 471),

(61) 4-aminobenzoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 472),

(62) 4-aminomethylbenzoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 473),

(63) pyrrole-3-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (compound number 474),

(64) pyrimidine-4-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 475),

(65) pyrimidine-2-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 479),

(66) Pyridazine-4-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 480),

(67) D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har-Trp-NH ₂ (Compound No. 481),

(68) D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Lys-Phe-NH ₂ (Compound No. 487),

(69) D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har-Phe-NH ₂ (Compound No. 488),

(70) D-Tyr-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 490),

(71) D-Tyr-D-Pya(4)-Asn-Trp-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 491),

(72) D-Tyr-D-Pya(4)-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 492),

(73) D-Tyr-D-Pya(4)-Thr-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 493),

(74) D-Tyr-D-Pya(4)-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 496),

(75) D-Tyr-D-Pya(4)-Asn-Ser-Cha-Ala-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 497),

(76) D-Tyr-D-Pya(4)-Asn-Ile-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 498),

(77) 3-phenylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 499),

(78) 3-phenylpropionyl-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 500),

(79) D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 501),

(80)D-Tyr-Pya(4)-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 502),

(81) D-Tyr-D-Trp-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 503),

(82) 6-aminocaproyl-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 504),

(83) 3-phenylpropionyl-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 505),

(84) 3-phenylpropionyl-Asn-Ile-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 506),

(85) 3-phenylpropionyl-Asn-Ser-Trp-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 507),

(86) 3-phenylpropionyl-Asn-Ser-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 508),

(87) Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 509),

(88) Ac-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 510),

(89) D-Tyr-D-Trp-Ala-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 511),

(90) D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 512),

(91) D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 513),

(92) D-Tyr-D-Phe-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 514),

(93) D-Tyr-D-Pya(4)-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 515),

(94)des((1)-Ac-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9]MS10 (Compound No. 516),

(95) des(1-3)-3-phenylpropionyl-[Hyp5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 517),

(96) des(1-3)-3-phenylpropionyl-[Cha6, Arg(Me)9, Trp10]MS10 (Compound No. 518),

(97)des(1-3)-phenylacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 519),

(98)des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7]MS10 (Compound No. 521),

(99) des(1-3)-benzoyl-[Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 522),

(100)des(1-3)-benzoyl-[Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 523),

(101)des(1-3)-3-phenylpropionyl-[Pro5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 524),

(102)des(1)-[D-Tyr2, D-Pya(4)3, Hyp5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 527),

(103)des(1)-[D-Tyr2, D-Pya(4)3, Pro5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 528),

(104)des(1)-[D-Tyr2, D-Pya(4)3, Tle5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 529),

(105)des(1)-[D-Tyr2, D-Pya(4)3, Phg5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 530),

(106)des(1-3)-3-phenylpropionyl-[Pic(2)5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 531),

(107)des(1-3)-3-phenylpropionyl-[Aze(2)5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 532),

(108)des(1-3)-3-phenylpropionyl-[D-Pro5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 533),

(109)des(1-3)-cyclopropanecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 534),

(110)des(1-3)-2-naphthoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 535),

(111) [Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 536),

(112) Arg-[Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 537),

(113) Arg-[Acp1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 538),

(114)des(1)-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 539),

(115)des(1)-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 540),

(116) D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 541),

(117) D-Arg-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 542),

(118) des(1-3)-benzoyl-[Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 545),

(119) des(1-3)-3-phenylpropionyl-[Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 546),

(120)des(1)-[D-Tyr2, D-Pya(4)3, Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 547),

(121)des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, 10Ψ, CSNH]MS10 (Compound No. 548),

(122) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 550),

(123) Ac-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 551),

(124) D-Dap-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 552),

(125) D-Nle-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 553),

(126) D-Arg-[β-Ala1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 554),

(127) D-Arg-[γ-Abu 1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me) 9, Trp10] MS10 (Compound No. 555),

(128) D-Arg-D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 556),

(129) D-Arg-D-Arg-D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 557),

(130)des(1)-Ac-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 558),

(131) des(1-2)-3-(4-hydroxyphenyl) propionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 559),

(132) D-Arg-[Acp1, D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 561),

(133)des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 562),

(134)des(1)-Ac-[D-Tyr2, D-Trp3, Aze(2)5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 563),

(135) des(1)-Ac-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 564),

(136) des(1)-benzoyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 565),

(137) des(1)-cyclopropanecarbonyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 566),

(138) des(1)-butyryl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 567),

(139) Ac-[D-Arg1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 568),

(140) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, 6Ψ7, CH2NH, Arg(Me)9, Trp10] MS10 (Compound No. 569),

(141) des(1)-Me-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 570),

(142)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9]MS10 (Compound No. 571),

(143)des(1)-[D-Trp2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 572),

(144) des(1)-Ac-[D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 573),

(145)des(1)-Ac-[D-Tyr2, D-Trp3, Gln4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 576),

(146) des(1)-Ac-[D-Tyr2, D-Trp3, Ser4, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 577),

(147) des(1)-Ac-[D-Tyr2, D-Trp3, Thr4, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 578),

(148)des(1)-Ac-[D-Tyr2, D-Trp3, Alb4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 579),

(149)des(1)-Ac-[D-Tyr2, D-Trp3, Ser(Me)5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 580),

(150)des(1)-Ac-[D-Tyr2, D-Trp3, Dap(Ac)4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 584),

(151)des(1)-Ac-[D-Tyr2, D-Trp3, Dap(For)4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 585),

(152)des(1)-Ac-[D-Tyr2, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 586),

(153)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Nal(2)10]MS10 (Compound No. 589),

(154) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Thi10] MS10 (Compound No. 590),

(155)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Tyr10]MS10 (Compound No. 591),

(156)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Phe(4F)10]MS10 (Compound No. 592),

(157)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Hph10]MS10 (Compound No. 594),

(158)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Cha10]MS10 (Compound No. 595),

(159)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Leu10]MS10 (Compound No. 596),

(160)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 597),

(161) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Arg(Me)9, Trp10] MS10 (Compound No. 598),

(162) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Orn9, Trp10] MS10 (Compound No. 599),

(163) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Trp10] MS10 (Compound No. 600),

(164) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, Arg(Me)9, Trp10] MS10 (Compound No. 601),

(165)des(1)-Ac-[D-NMeTyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 Compound No. 602),

(166)des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 603),

(167)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Tos)9, Trp10]MS10 (Compound No. 604),

(168)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(NO2)9, Trp10]MS10 (Compound No. 605),

(169)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me2)asym9, Trp10]MS10 (Compound No. 607),

(170)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me2)sym9, Trp10]MS10 (Compound No. 608),

(171)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Et)9, Trp10]MS10 (Compound No. 609),

(172)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys(Me2)9, Trp10]MS10 (Compound No. 610),

(173)des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 611),

(174) des(1)-For-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 612),

(175) des(1)-propionyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 613),

(176) des(1)-amidino-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 614),

(177)des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 615),

(178)des(1)-Ac-[D-Ala2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 616),

(179)des(1)-Ac-[D-Leu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 617),

(180)des(1)-Ac-[D-Phe2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 618),

(181)des(1)-Ac-[D-Nal(1)2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 619),

(182)des(1)-Ac-[D-Nal(2)2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 620),

(183)des(1)-Ac-[D-Lys2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 621),

(184)des(1)-Ac-[D-Glu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 622),

(185)des(1)-Ac-[D-Tyr2, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 623),

(186)des(1)-Ac-[D-Tyr2, Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 624),

(187)des(1)-Ac-[D-Tyr2, D-Ala3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 625),

(188)des(1)-Ac-[D-Tyr2, D-Leu3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 626),

(189)des(1)-Ac-[D-Tyr2, D-Phe3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 627),

(190)des(1)-Ac-[D-Tyr2, D-Thr3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 628),

(191)des(1)-Ac-[D-Tyr2, D-Lys3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 629),

(192)des(1)-Ac-[D-Tyr2, D-Glu3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 630),

(193)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Ala6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 631),

(194)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Leu6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 632),

(195)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Lys6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 633),

(196)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Glu6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 634),

(197)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Pya(4)6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 635),

(198)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, NMePhe6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 636),

(199)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 637),

(200)des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 638),

(201) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys9, Trp10] MS10 (Compound No. 639),

(202)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ala8, Arg(Me)9, Trp10]MS10 (Compound No. 641),

(203)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Val8, Arg(Me)9, Trp10]MS10 (Compound No. 642),

(204)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Phe8, Arg(Me)9, Trp10]MS10 (Compound No. 643),

(205)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ser8, Arg(Me)9, Trp10]MS10 (Compound No. 644),

(206) des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Har9, Trp10] MS10 (Compound No. 645),

(207)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Har(Me)9, Trp10]MS10 (Compound No. 646),

(208)des(1)-Ac-[D-Tyr2, D-Trp3, Asp4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 647),

(209) [Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 648),

(210) Ac-[Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 649),

(211) [D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 650),

(212) Ac-[D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 651),

(213) pGlu-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 652),

(214)des(1)-Ac-[D-Tyr2, D-Trp3, D-Asn4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 653),

(215)des(1)-Ac-[D-Tyr2, D-Trp3, D-Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 654),

(216)des(1)-Ac-[D-Tyr2, D-Trp3, NMeAsn4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 655),

(217)des(1)-Ac-[D-Tyr2, D-Trp3, NMeSer5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 656),

(218)des(1)-Ac-[D-Tyr2, Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 657),

(219)des(1)-Ac-[D-Tyr2, D-Pya(2)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 658),

(220)des(1)-Ac-[D-Tyr2, D-Trp3, allo-Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 659),

(221)des(1)-Ac-[D-Tyr2, D-Pya(3)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 660),

(222)des(1)-Ac-[D-Tyr2, D-Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 661),

(223)des(1)-Ac-[D-Tyr2, Tic3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 662),

(224)des(1)-Ac-[D-Trp2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 663),

(225)des(1)-Ac-[Tyr2, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No.

(226)des(1-2)-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 665),

(227)des(1-2)-Ac-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 666),

(228)des(1-2)-hexanoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 667),

(229) des(1-2)-cyclohexanecarbonyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 668),

(230)des(1-2)-benzoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 669),

(231) des(1-2)-3-pyridinepropionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 670),

(232) des(1-2)-adipyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (compound number 671), (233) des(1)-Ac-[D -Tyr2, NMeTrp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 672),

(234)des(1-2)-6-aminocaproyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 674),

(235) [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 (Compound No. 675),

(236)Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 676),

(237)Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Nva8, Arg(Me)9, Trp10]MS10 (Compound No. 677)

(238)Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ile8, Arg(Me)9, Trp10]MS10 (Compound No. 678)

(239)des(1-2)-Amidino-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 679)

(240)des(1-2)-glycoloyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 680)

(241)des(1)-glycoloyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 681)

(242)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Gln8, Arg(Me)9, Trp10]MS10 (Compound No. 682)

(243)des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9]MS10 (Compound No. 685)

(244)des(1)-Ac-[D-Tyr2, D-Trp3, Gly4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 686)

(245)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Pya(4)9, Trp10]MS10 (Compound No. 688)

(246)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, D-Trp10]MS10 (Compound No. 689)

(247)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 691)

(248)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Trp6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 692)

(249)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr(Me)6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 693)

(250)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Nal(2)6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 694)

(251)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Thi6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 695)

(252)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Cha6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 696)

(253)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Abu8, Arg(Me)9, Trp10]MS10 (Compound No. 698)

(254)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, γMeLeu8, Arg(Me)9, Trp10]MS10 (Compound No. 699)

(255)des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Aib8,, Arg(Me)9, Trp10]MS10 (Compound No. 700)

(256)des(1)-Ac-[D-Tyr2, D-Trp3, Dap4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 701)

(257)des(1)-Ac-[D-Tyr2, D-Trp3, Asp(NHMe)4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 702)

(258)des(1)-Ac-[D-Tyr2, D-Trp3, Asp(NMe2)4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 703).

(54) The drug as described in (48) to (53), which is a down-regulator of gonadotropins or sex hormones.

(55) The drug as described in (48) to (53), which is a down-regulator of human OT7T175 (transferin receptor) protein consisting of the amino acid sequence shown in SEQ ID NO: 9.

(56) The drug as described in (48) to (55), which is a drug for preventing or treating hormone-dependent cancer.

(57) A method for inhibiting gonadotropin secretion or sex hormone secretion, which comprises administering an effective dose of the transferin derivative (III) or a salt thereof as described in (48), or a prodrug thereof, to a mammal.

(58) A method for down-regulating gonadotropins or sex hormones, comprising administering to mammals an effective dose of the transferin derivative (III) or a salt thereof as described in (48), or a prodrug thereof.

(59) A method for down-regulating the human OT7T175 (transferin receptor) protein consisting of the amino acid sequence shown in SEQ ID NO: 9, which comprises administering an effective dose of the transferin derivative as described in (48) or their salts, or their prodrugs.

(60) A method for preventing or treating hormone-dependent cancer, which comprises administering an effective dose of the transferin derivative or salt thereof as described in (48), or a prodrug thereof, to a mammal.

(61) Use of the transferin derivative or salt thereof as described in (48), or a prodrug thereof, in the manufacture of a medicament for inhibiting gonadotropin secretion or a medicament for inhibiting sex hormone secretion.

(62) Use of the transferin derivatives or salts thereof as described in (48), or their prodrugs, in the preparation of down-regulators for gonadotropins or sex hormones.

(63) The transferin derivatives or salts thereof as described in (48), or their prodrugs are used in the preparation of human OT7T175 (transferin receptor) protein consisting of the amino acid sequence shown in SEQ ID NO: 9 Use in conditioning.

(64) Use of the transferin derivative or salt thereof as described in (48), or a prodrug thereof, in the manufacture of a medicament for preventing or treating hormone-dependent cancer.

(65) A transferin derivative represented by the following formula:

XX0-XX2-XX3-XX4-XX5-XX6-AzaGly-XX8-XX9-XX10-NH ₂

(in:

XX0 represents formyl, C _1-6 alkanoyl, cyclopropanecarbonyl, 6-(acetyl-D-arginylamino) hexanoyl, 6-((R)-2,3-diaminopropionylamino) hexyl Acyl, 6-(D-norleucylamino)hexanoyl, 4-(D-arginylamino)butyryl, 3-(4-hydroxyphenyl)propionyl, glycyl, tyrosyl, acetyl Glycyl, acetyltyrosyl, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3-(pyridin-3-yl)propionyl, adipyl, or 6-aminocaproyl ;

XX2 means Tyr, D-Tyr, D-Ala, D-Leu, D-Phe, D-Lys, D-Trp or bond arm;

XX3 represents Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D-3-pyridylalanine or D-4-pyridylalanine;

XX4 represents Asn, 2-amino-3-ureidopropionic acid, N ^β -formyl diaminopropionic acid or N ^β -acetyl diaminopropionic acid;

XX5 means Ser, Thr or Val;

XX6 represents Phe, Tyr, Trp, Tyr(Me), Thi, Nal(2), Cha, 4-pyridylalanine or 4-fluorophenylalanine;

AzaGly means azaglycine;

XX8 means Leu, Nva or Val;

XX9 represents Arg, Orn, Arg(Me) or Arg(symMe2);

XX10 represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine, or 4-fluorophenylalanine), or a salt thereof.

(66) D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 305),

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 385),

D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 501),

Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 509),

D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 512),

Ac-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 516),

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 540),

D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 541),

Benzoyl-Asn-Ser-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 545),

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-PheΨ(CSNH)NH ₂ (Compound No. 548),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 550),

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 551),

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 552),

D-Nle-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 553),

D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 555),

Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 558),

3-(4-hydroxyphenyl)propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 559),

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 562),

Ac-D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 564),

Cyclopropanecarbonyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 566),

Butyryl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 567),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 571),

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 579),

Ac-D-Tyr-D-Trp-Asn-Ser(Me)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 580),

Ac-D-Tyr-D-Trp-Dap(Ac)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 584),

Ac-D-Tyr-D-Trp-Dap(For)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 585),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂ (Compound No. 589),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Thi-NH ₂ (Compound No. 590),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Tyr-NH ₂ (Compound No. 591),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂ (Compound No. 592),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Orn-Trp-NH ₂ (Compound No. 599),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂ (Compound No. 600),

Ac-D-NMeTyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp- _NH2 (Compound No. 602),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(symMe2)-Trp-NH ₂ (Compound No. 608),

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 612),

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 613),

Ac-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 615),

Ac-D-Ala-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 616),

Ac-D-Leu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 617),

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 618),

Ac-D-Lys-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 621),

Ac-D-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 623),

Ac-D-Tyr-D-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 625),

Ac-D-Tyr-D-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 626),

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 627),

Ac-D-Tyr-D-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 629),

Ac-D-Tyr-D-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 630),

Ac-D-Tyr-D-Trp-Asn-Thr-Pya(4)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 635),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 637),

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 638),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Val-Arg(Me)-Trp-NH ₂ (Compound No. 642),

Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 648),

Ac-Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 649),

D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp- _NH2 (Compound No. 650),

Ac-D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 651),

pGlu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp- _NH2 (Compound No. 652),

Ac-D-Tyr-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 657),

Ac-D-Tyr-D-Pya(2)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 658),

Ac-D-Tyr-D-Pya(3)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 660),

Ac-D-Tyr-Tic-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 662),

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 663),

Ac-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 666),

Hexanoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 667),

3-pyridinepropionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 670),

Adipyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 671),

Ac-D-Tyr-NMeTrp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 672),

6-aminocaproyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 674), or a salt thereof.

(67) Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 550),

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 551),

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 552),

Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 558),

3-(4-hydroxyphenyl)propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 559),

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 562),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 571),

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 579),

Ac-D-Tyr-D-Trp-Dap(For)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 585),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂ (Compound No. 589),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂ (Compound No. 592),

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 612),

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 613),

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 618),

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 627),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 637),

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 638),

Ac-D-Tyr-D-Pya(2)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 658),

Ac-D-Tyr-D-Pya(3)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 660),

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 663), or a salt thereof.

(68) The drug as described in (48) above, which is an immunopotentiator (a preventive agent for infection after bone marrow transplantation, an immunopotentiator against cancer).

(69) The drug as described in (48) above, which is a preventive/therapeutic agent for bullbospinal muscular atrophy.

(70) The drug as described in (48) above, which is a prophylactic/therapeutic agent for ovarian protection.

(71) The drug as described in (48) above, which is a preventive/therapeutic agent for benign prostatic hypertrophy (BPH).

(72) The drug as described in (48) above, which is a preventive/therapeutic agent for gender identity disorder.

(73) The drug as described in (48) above, which is a preventive/therapeutic agent for in vitro fertilization (IVF).

A brief description of the drawings

Fig. 1 shows the results of evaluating the chemotaxis inhibitory activity of compounds Nos. 322, 305, 303, 286, 232, and 141 using CHO cells expressing hOT7T175. On the abscissa, FBS- means no FBS added, FBS+ means added FBS, 322 means added No. 322 compound, 305 means added No. 305 compound, 303 means added No. 303 compound, 286 means added No. 286 compound, No. 232 indicates the addition of compound No. 232, 141 indicates the addition of compound No. 141, (1-54) indicates the addition of transferins (1-54), and (45-54) indicates the addition of transferins 45-54. The ordinate represents the relative activity when the chemotactic activity added with FBS is taken as 100%

Figure 2 shows the results of evaluating the tumor growth inhibitory activity of No. 322 compound and metastasin (1-54) using tumorigenic mice with human-derived colon cancer cell line SW620, where the numerical values represent (mean )±(standard error). Symbols hollow diamonds, hollow circles, solid circles and solid squares represent the results when vehicle (distilled water), compound No. 322 (0.1 mM), compound No. 322 (1 mM) and transferin (transferin 1-54) were added, respectively. The abscissa indicates the days after inoculation. The bar graph on the abscissa indicates the dosing cycle. The ordinate represents tumor size (mm ³ ).

Figure 3 shows the results of evaluating the tumor growth inhibitory activity of No. 305 compound and metastasin (1-54) using tumorigenic mice with human-derived colon cancer cell line SW620, where the values represent (mean )±(standard error). The symbols hollow rhombus, hollow circle, solid circle and solid square represent the results when vehicle (distilled water), compound No. 305 (0.1 mM), compound No. 305 (1 mM) and transferin (transferin 1-54) were added, respectively. The abscissa indicates the days after inoculation. The bar graph on the abscissa indicates the dosing cycle. The ordinate represents tumor size (mm ³ ).

Fig. 4 shows the results of monitoring changes in blood glucose level when transferin was injected intravenously to rats under non-anesthetized state. In the figure, the symbols hollow circles, solid triangles, solid circles and solid diamonds represent the blood glucose levels of the normal saline group, the 17nmol/kg transferin group, the 80nmol/kg transferin group and the 170nmol/kg transferin group respectively. Values represent (mean±SE) (n=5). The symbol ^* indicates that the P value is less than or equal to 0.05 when compared with the normal saline group, and the symbol ^** indicates that the P value is less than or equal to 0.01 when compared with the normal saline group.

Fig. 5 shows the results of monitoring changes in blood glucagon levels when transferin was injected intravenously to rats under non-anesthetized state. In the figure, the symbols hollow circles and solid circles represent blood glucagon levels in the normal saline group and the 80 nmol/kg transferin group, respectively. Values represent (mean ± SE) (n = 6-9). The symbol ^* indicates that the P value is less than or equal to 0.05 when compared with the normal saline group, and the symbol ^** indicates that the P value is less than or equal to 0.01 when compared with the normal saline group.

Fig. 6 shows the results of changes in blood insulin levels monitored when transferin was injected intravenously to rats under non-anesthetized state. In the figure, the hollow circles and solid circles represent the blood insulin levels of the normal saline group and the 80 nmol/kg transferin group respectively. Values represent (mean ± SE) (n = 6-9), respectively.

Fig. 7 shows the results of monitoring changes in blood corticosterone level when transferin was injected intravenously to rats under non-anesthetized state. In the figure, the hollow circles and solid circles represent the blood corticosterone levels of the normal saline group and the 80 nmol/kg transferin group respectively. Values represent (mean±SE) (n=4-5).

Fig. 8 shows the results of monitoring changes in thyroid hormone (T3) levels when transferin was injected intravenously to rats under non-anesthetized state. In the figure, the symbols hollow circle and solid circle represent the thyroid hormone (T3) levels of the normal saline group and the 80 nmol/kg transferin group respectively. Values represent (mean±SE) (n=4-5).

Fig. 9 shows the results of monitoring changes in blood glucose level when transferin was injected intravenously to rats under non-anesthetized state. In the figure, the symbols hollow circles and solid circles represent blood glucose levels in the normal saline group and the 80 nmol/kg transferin group, respectively. Values represent (mean ± SE) (n = 6-9). The symbol ^* indicates that the P value is less than or equal to 0.05 when compared with the saline group.

Fig. 10 shows the results of monitoring changes in blood glucose levels when the transferin derivatives were intravenously injected into rats under non-anesthetized state. In the figure, the symbols hollow circle, solid circle and solid triangle represent the blood glucose levels of the normal saline group, the 80nmol/kg KiSS1-305 group and the 80nmol/kg transferin group respectively. The symbol ^* indicates that the P value is less than or equal to 0.05 when compared with the normal saline group, and the symbol ^** indicates that the P value is less than or equal to 0.01 when compared with the normal saline group.

Figure 11 shows the results of monitoring changes in blood glucagon levels of rats intravenously injected with transferin in a non-anesthetized state. In the figure, the symbols hollow circles, solid circles and solid triangles respectively represent the hyperthyroidism in the blood of the normal saline group, the KiSS1-305 (compound number 305) group of 80nmol/kg and the KiSS1-322 (compound number 322) group of 80nmol/kg. glucagon levels. Values represent (mean+SE) (n=5). The symbol ^* indicates that the P value is less than or equal to 0.05 when compared with the saline group.

Figure 12 shows the levels of estradiol contained in rat plasma. In the figure, the ordinate and the abscissa represent the level of estradiol and each administration group, respectively.

Figure 13 shows the levels of progesterone contained in rat plasma. In the figure, the ordinate and the abscissa represent the level of estradiol and each administration group, respectively.

Fig. 14 shows the change of FSH level in the blood of immature rats after transferrin injection.

Fig. 15 shows the change of LH level in the blood of immature rats after transferin injection.

Fig. 16 shows the change of progesterone level in the blood of immature rats after injection of transferrin.

Fig. 17 shows the change of FSH level in blood of rats after transferin injection.

Fig. 18 shows changes in blood LH levels of rats after transferin injection.

Fig. 19 shows the change of blood testosterone level in rats after transferin injection.

Fig. 20 shows the number of oocytes per rat in each group tested in Example 13. In the figure, the symbol solid diamond represents the data of each rat, and the symbol solid square represents the average value of each group.

Figure 21 shows the detection of blood estradiol levels in each administration group in Example 13. In the figure, the symbol solid triangle represents the data of each rat, and the symbol solid square represents the average value of each group.

Figure 22 shows the detection of blood progesterone levels in each administration group in Example 13. In the figure, the symbol solid triangle represents the data of each rat, and the symbol solid square represents the average value of each group.

The best way to practice the invention

In the above general formula, n represents 0 or 1; ^W1 represents N, CH or O (provided that when ^W1 is N or CH, then n represents 1, and when ^W1 represents O, then n represents 0) ; W ² represents N or CH; Z ¹ , Z ³ , Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group; Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S ;

Wherein, when Z ² , Z ⁴ , Z ⁶ or Z ⁸ represent a hydrogen atom, then the structures of the parts represented by >C=Z ² , >C=Z ⁴ , >C=Z ⁶ or >C=Z ⁸ represent > _CH2 structure.

The C _1-3 alkyl used includes methyl, ethyl, propyl and isopropyl.

W ¹ is preferably N, and W ² is preferably CH.

The preferred combination of Z ¹ to Z ⁸ also includes that Z ¹ and Z ³ represent a hydrogen atom, each of Z ⁵ and Z ⁷ represents a hydrogen atom or a C _1-3 alkyl group, and Z ² , Z ⁴ , Z ⁶ and Z Each of ^{the 8} means O or S.

More preferably, the combination of Z ¹ to Z ⁸ includes:

(a) A case where ^Z1 is a hydrogen atom, ^Z3 is a hydrogen atom, ^Z5 is a hydrogen atom, and ^Z7 is a hydrogen atom, and ^Z2 is O, ^Z4 is O, ^Z6 is O, and ^Z8 is O ;

(b) A case where ^Z1 is a hydrogen atom, ^Z3 is a hydrogen atom, ^Z5 is a hydrogen atom, and ^Z7 is a hydrogen atom, and ^Z2 is O, ^Z4 is O, ^Z6 is O, and ^Z8 is S ;

(c) wherein Z ¹ and Z ³ are hydrogen atoms, and Z ⁵ is hydrogen atoms, Z ⁷ is methyl, and Z ² is O, and Z ⁴ is O, Z ⁶ is O and Z ⁸ is O; etc. . Among them, (a) and (b) are preferable.

R ¹ represents (1) a hydrogen atom, (2)) a C _1-8 alkyl group, and the C _1-8 alkyl group is optionally selected from an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted The substituent of the aromatic ring group is substituted, (3) cyclic or chain C _1-10 alkyl, or (4) C _1-10 alkyl consisting of cycloalkyl and chain alkyl, or (5) An optionally substituted aromatic ring group. Among them, preferred R ¹ includes (1) a hydrogen atom or (2) a C _1-8 alkyl group, and the C _1-8 alkyl group is optionally selected from an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and The substituent of the optionally substituted aromatic ring group is substituted, more preferably includes (1) a hydrogen atom or (2)) a C _1-8 alkyl group, the C _1-8 alkyl group is selected from an optionally substituted amino group Substituents of formyl, optionally substituted hydroxy, and optionally substituted aromatic ring groups are substituted.

The "C _1-8 alkyl" used includes, for example: chain C _1-8 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc., and cyclic C _3-8 alkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. C _1-3 alkyl groups such as methyl, ethyl and the like are especially preferred.

The "optionally substituted carbamoyl" used includes, for example, carbamoyl, mono-C _1-6 alkylcarbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _{1-6 6} Alkylcarbamoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), mono- or _di -C arylcarbamoyl (for example, benzene ylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.) and mono- or di-5 or 7-membered heterocyclic carbamoyl (for example, 2-pyridylcarbamoyl, 3 -pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), the heterocyclic carbamoyl contains 1 to 4 heteroatoms selected from one or two of nitrogen, sulfur and oxygen atoms.

The "optionally substituted hydroxy" used includes, for example: hydroxyl, optionally substituted C _1-6 alkoxy, optionally substituted C _6-14 aryloxy, optionally substituted C _7-16 aralkyloxy wait. The "optionally substituted C _1-6 alkoxy", "optionally substituted C _6-14 aryloxy" and "optionally substituted C _7-16 aralkoxy" used are groups described later "Optionally substituted C _1-6 alkoxy", "optionally substituted C _6-14 aryloxy" and "optionally substituted C _7-16 aralkoxy" in A.

The "aromatic ring group" in the "optionally substituted aromatic ring group" includes, for example, an aromatic hydrocarbon group, an aromatic heterocyclic group, an aromatic fused ring group, an aromatic fused heterocyclic group, and the like.

The "aromatic hydrocarbon group" used includes, for example, C _6-14 aryl groups such as phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, and cyclooctatetraenyl.

The "aromatic heterocyclic group" used includes, for example, 5 to 14-membered, preferably 5 to 10-membered, and more preferably 5 to 6-membered aromatic heterocyclic groups, which, in addition to carbon atoms, also contain 1 to 4 heteroatoms, the heteroatoms are selected from 1 or 2 of nitrogen, sulfur and oxygen atoms. Specific examples include thienyl (for example, 2-thienyl, 3-thienyl), furyl (for example, 2-furyl, 3-furyl), pyridyl (for example, 2-pyridyl, 3-pyridine base, 4-pyridyl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (for example, 2-oxazolyl, 4-oxazolyl), pyrazinyl, Pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazole base, 4-imidazolyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl ), isothiazolyl (for example, 3-isothiazolyl), isoxazolyl (for example, 3-isoxazolyl) and the like.

The "aromatic fused ring group" used includes C _8-14 aromatic condensed ring groups such as naphthyl (for example, 1-naphthyl, 2-naphthyl), anthracenyl (for example, 2-anthracenyl, 9-anthracenyl), etc. Ring base.

The "aromatic condensed heterocyclic group" used includes, for example: 5 to 14 membered (preferably 5 to 10 membered) bicyclic or tricyclic aromatic heterocyclic group, except that the aromatic heterocyclic group contains 3 to 11 carbons In addition to atoms, 1 to 4 heteroatoms are selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, or from 7 to 14 (preferably 5 to 10) rings. A monovalent group obtained by removing an optional hydrogen atom from a 10-membered aromatic bridged heterocyclic ring containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from One or two of nitrogen, sulfur and oxygen atoms. These groups used are exemplified by quinolinyl (for example, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (for example, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), indolyl (for example, 1-indolyl, 2-indolyl, 3-indolyl), 2-benzothiazolyl, benzo[b]thienyl (eg, 2-benzo[b]thienyl, 3-benzo[b]thienyl), benzo[b]thienyl furyl (eg, 2-benzo[b]furyl, 3-benzo[b]furyl) and the like.

The "substituent" used for the "aromatic ring group" includes a substituent selected from the substituent A described later.

For R ¹ , a hydrogen atom, carbamoylmethyl, 2-carbamoylethyl, hydroxymethyl, 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolylmethyl, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexylmethyl, phenyl, acetoxymethyl, methoxymethyl, etc. Preferred are hydroxymethyl, 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 3-indolylmethyl, methyl, isobutyl, etc., more preferably hydroxymethyl, 1-hydroxyethyl, etc. .

R ² represents (1) a hydrogen atom, (2) a cyclic or chain C _1-10 alkyl group, (3) a C _1-10 alkyl group formed from a cycloalkyl group and an alkanyl group, or (4) a C _{10 group -8} alkyl, the C _1-8 alkyl is optionally substituted by an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic ring group. Among them, preferred are (1) a hydrogen atom, (2) a cyclic or chain C _1-10 alkyl group, or (3) a C _1-10 alkyl group formed from a cycloalkyl group and an alkanyl group. Especially preferred is (3) a C _1-10 alkyl group formed from a cycloalkyl group and an alkanyl group.

The cyclic C _1-10 alkyl group used includes, for example, C _3-8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Examples of chain C _1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Hexyl, heptyl, octyl, nonanyl, decanyl, etc.

The C _1-10 alkyl formed from cycloalkyl and chain alkyl includes, for example: C _3-7 cycloalkyl-C _1-3 alkyl such as cyclopentylmethyl, cyclohexylmethyl and the like.

Examples of ^R include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexylmethyl, benzyl, hydroxymethyl, 2-carbamoyl Ethyl, tert-amyl and the like; among them, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl and the like are preferred. More preferred are propyl, isopropyl, isobutyl and the like.

R ³ means;

(1) C _1-8 alkyl, said C _1-8 alkyl has an optionally substituted basic group and optionally has other substituents,

(2) Aralkyl groups having optionally substituted basic groups and optionally further substituents,

(3) C _1-4 alkyl, the C _1-4 alkyl has a non-aromatic cyclic hydrocarbon group with no more than 7 carbon atoms, and the non-aromatic cyclic hydrocarbon group has an optionally substituted basic group and any optionally have other substituents, or

(4) C _1-4 alkyl, the C _1-4 alkyl has a non-aromatic heterocyclic group with no more than 7 carbon atoms, and the non-aromatic heterocyclic group has an optionally substituted basic group and optionally have other substituents.

The "optionally substituted basic group" used includes, for example, (1) guanidino, which optionally has 1 or 2 selected from C _1-6 alkyl, C _1-6 acyl, etc. (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, acetyl group, propionyl group, etc.), (2) amino group, the amino group optionally has 1 to 3 selected from C _1-6 alkyl, Substituents of C _1-6 acyl, etc. (for example, methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl, etc.), (3) C _1-6 alkylcarbonylamino (for example, , acetylamino), the C _1-6 alkylcarbonylamino is optionally substituted by guanidino, and the guanidino optionally has 1 or 2 selected from C _1-6 alkyl, C _1-6 acyl, etc. (for example , methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl, etc.), (4) C _1-6 alkylcarbonylamino (for example, acetylamino), the C _{1 -6} alkylcarbonylamino is optionally substituted by amino, which optionally has 1 to 3 members selected from C _1-6 alkyl, C _1-6 acyl, etc. (for example, methyl, ethyl, propyl, iso Propyl, butyl, acetyl, propionyl, etc.) substituents. Among them, preferred guanidino, N-methylguanidino, N,N-dimethylguanidino, N,N'-dimethylguanidino, N-ethylguanidino, N-acetylguanidino, amino, N-methylamino, N,N-dimethylamino, aminoacetamido, guanidinoacetamido, amidino, etc.

The "other substituents" other than the "optionally substituted basic group" used include substituents selected from the substituent A described later.

Examples of "C _1-8 alkyl" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl base, hexyl, heptyl, octyl, etc.

The "aralkyl group" used includes, for example, C _7-16 aralkyl groups such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2- Diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylmethyl, 3-biphenylmethyl, 4-biphenylmethyl Base etc.

The "non-aromatic cyclic hydrocarbon group having not more than carbon atoms" used includes, for example, C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The "non-aromatic heterocyclic group having not more than 7 carbon atoms" used includes, for example, 5- to 10-membered non-aromatic heterocyclic groups, etc., except that the non-aromatic heterocyclic group contains 1 to 7 carbon atoms In addition, it also contains 1 to 4 heteroatoms, and the heteroatoms are selected from 1 or 2 kinds of nitrogen, sulfur and oxygen atoms. Specific examples of use are pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (e.g., 2-oxazolidinyl), imidazolidinyl (e.g. , 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl) , piperazinyl (eg, 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino, and the like.

Examples of the "C _1-4 alkyl" used include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

As R ³ , for example, (1) 3-guanidinopropyl, 3-(N-methylguanidino)propyl, 3-(N,N-dimethylguanidino)propyl, 3-(N, N'-dimethylguanidino)propyl, 3-(N-ethylguanidino)propyl, 3-(N-propylguanidino)propyl, 3-(N-acetylguanidino)propyl , 4-guanidinobutyl, 4-(N-methylguanidino)butyl, 2-guanidinoethyl, 2-(N-methylguanidino)ethyl, 4-aminobutyl, 4-( N-methylamino)butyl, 4-(N,N-dimethylamino)butyl, 3-aminopropyl, 2-aminoethyl, aminomethyl, aminoacetamidomethyl, guanidinoacetamidomethyl , 2-(guanidinocarbonyl) ethyl, (2) 4-guanidinobenzyl, 4-aminobenzyl, (3) 4-guanidinocyclohexylmethyl, 4-aminocyclohexylmethyl, (4) 1-amidinopiperidin-4-ylmethyl, 4-pyridylmethyl, etc., preferably 3-guanidinopropyl, 3-(N-methylguanidino)propyl, 3-(N,N- Dimethylguanidino)propyl, 3-(N,N'-dimethylguanidino)propyl, 3-(N-ethylguanidino)propyl, 3-(N-propylguanidino)propyl Base, 3-(N-acetylguanidino)propyl, 4-guanidinobutyl, 4-(N-methylguanidino)butyl, 2-guanidinoethyl, 2-(N-methylguanidine Base) ethyl, 4-aminobutyl, 4-(N-methylamino)butyl, 4-(N,N-dimethylamino)butyl, 3-aminopropyl, 2-aminoethyl, 4- Aminobenzyl, aminoacetamidomethyl, guanidinoacetamidomethyl, etc., more preferably 3-guanidinopropyl, 3-(N-methylguanidino)propyl, 3-(N,N-dimethyl guanidino) propyl, 3-(N, N'-dimethylguanidino) propyl, 3-(N-ethylguanidino) propyl, 3-(N-acetylguanidino) propyl, 4-guanidinobutyl, 4-(N-methylguanidino)butyl, 2-guanidinoethyl, 4-aminobutyl and the like.

R ⁴ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following group:

(1) Optionally substituted C _6-12 aromatic hydrocarbon groups;

(2) An optionally substituted 5- to 14-membered aromatic heterocyclic group formed of 1-7 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atoms;

(3) optionally substituted C _8-14 aromatic fused ring groups;

(4) An optionally substituted 5- to 14-membered aromatic condensed heterocyclic group consisting of 3-11 carbon atoms and heteroatoms, the heteroatoms being selected from nitrogen, oxygen and sulfur atoms;

(5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and

(6) an optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms; and, preferably a C _1-4 alkyl group, the C _1-4 alkyl group being substituted by a substituent selected from the following:

(1) Optionally substituted C _6-12 aromatic hydrocarbon groups;

(2) An optionally substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, and the heteroatoms are selected from nitrogen, oxygen and sulfur atoms;

(3) optionally substituted C _8-14 aromatic fused ring groups;

(4) An optionally substituted 5- to 14-membered aromatic condensed heterocyclic group consisting of 3-11 carbon atoms and heteroatoms, the heteroatoms being selected from nitrogen, oxygen and sulfur atoms;

(5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms; and

(6) An optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms.

Examples of the "C _1-4 alkyl" used include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

The "C _6-12 aromatic hydrocarbon group" used includes, for example, monocyclic C _6-12 aromatic hydrocarbon groups such as phenyl, cyclooctatetraenyl and the like.

The "5 to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur atoms" includes, for example, 5 to 14-membered, preferably 5-10-membered, more preferably 5- or 6-membered monocyclic aromatic heterocyclic group, the 5- or 6-membered monocyclic aromatic heterocyclic group contains 1 to 7 carbon atoms to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms. Specific examples used are thienyl (e.g., 2-thienyl, 3-thienyl), furyl (e.g., 2-furyl, 3-furyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl base, 4-pyridyl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (for example, 2-oxazolyl, 4-oxazolyl), pyrazine Base, pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (for example, 1-imidazolyl, 2- imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl group), isothiazolyl (for example, 3-isothiazolyl), isoxazolyl (for example, 3-isoxazolyl) and the like.

The "C _8-14 aromatic condensed ring group" used includes, for example, naphthyl (eg, 1-naphthyl, 2-naphthyl), anthracenyl (eg, 2-anthryl, 9-anthryl) and the like.

The "optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur "Atom" includes, for example, a 5 to 14 membered (preferably 5 to 10 membered) bicyclic or tricyclic aromatic heterocyclic group containing, in addition to 3 to 11 carbon atoms, 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, or from 7 to 10 membered aromatic bridges in 5 to 14 membered (preferably 5 to 10 membered) rings Monovalent radicals obtained by removing one optional hydrogen atom from heterocyclic rings, said 5 to 14 membered ring containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen 1 or 2 of the atoms. Specific examples used are quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 8-quinolinyl), isoquinolinyl (e.g., 1 -isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), indolyl (for example, 1-indolyl, 2-indolyl, 3-indole base), 2-benzothiazolyl, benzo[b]thienyl, (for example, 2-benzo[b]thienyl, 3-benzo[b]thienyl), benzo[b]furyl ( For example, 2-benzo[b]furyl, 3-benzo[b]furyl) and the like.

The "non-aromatic cyclic hydrocarbon group having not more than 7 carbon atoms" used includes, for example, C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The "non-aromatic heterocyclic group having not more than 7 carbon atoms" used includes, for example, 5- to 10-membered non-aromatic heterocyclic groups which contain, in addition to 1 to 7 carbon atoms, Contains 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, such as pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl base), oxazolidinyl (for example, 2-oxazolidinyl), imidazolinyl (for example, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (for example, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (for example, 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpho Lino, etc.

For these "C _6-12 aromatic hydrocarbon groups", "5- to 14-membered aromatic heterocyclic groups, said to be composed of 1-7 carbon atoms and heteroatoms, said heteroatoms being selected from nitrogen, oxygen and sulfur atoms" , "C _8-14 aromatic condensed ring group", "5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms, and the heteroatoms are selected from The substituents used from nitrogen, oxygen and sulfur atoms", "non-aromatic cyclic hydrocarbon group having up to 7 carbon atoms" and "non-aromatic heterocyclic group having up to 7 carbon atoms" include, for example, those selected from the following Substituents: oxo, halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy groups (for example, methylenedioxy, ethylenedioxy, etc.), Nitro, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 cycloalkane Base, optionally substituted C _6-14 aryl, optionally substituted C _7-16 aralkyl, optionally substituted C _1-6 alkoxy, hydroxyl, optionally substituted C _6-14 aryloxy , optionally substituted C _7-16 aralkyloxy, mercapto, optionally substituted C _1-6 alkylthio, optionally substituted C _6-14 arylthio, optionally substituted C _7-16 arane Thio, optionally substituted amino [amino, optionally substituted mono- or di-C _1-6 alkyl-amino (for example, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino etc.), optionally substituted mono- or di-C _2-6 alkenyl-amino (for example, vinylamino, propenylamino, isopropenylamino), optionally substituted C _2-6 alkynylamino (for example , 2-butyn-1-yl-amino, 4-pentyn-1-yl-amino, 5-hexyn-1-yl-amino), optionally substituted mono- or di-C _3-8 cycloalkyl -amino (for example, cyclopropylamino, cyclohexylamino), optionally substituted C _6-14 arylamino (for example, phenylamino, diphenylamino, naphthylamino), optionally substituted C _{1- 6} alkoxyamino (for example, methoxyamino, ethoxyamino, propoxyamino, isopropoxyamino), formylamino, optionally substituted C _1-6 alkylcarbonylamino (for example, acetyl amino, propionylamino, pivalylamino, etc.), optionally substituted C _3-8 cycloalkylcarbonylamino (for example, cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, etc.), optionally Substituted C _6-14 aryl-carbonylamino (for example, benzoylamino, naphthoylamino, etc.), optionally substituted C _1-6 alkoxy-carbonylamino (for example, methoxycarbonylamino, ethoxy carbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), optionally substituted C _1-6 alkylsulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino, etc.), optionally substituted C _6-14 arylsulfonylamino (for example, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.)], formyl, carboxy, optionally substituted C _1-6 alkane acetylcarbonyl (for example, acetyl, propionyl, pivaloyl, etc.), optionally substituted C _3-8 cycloalkylcarbonyl (for example, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl -cyclohexyl-carbonyl, etc.), optionally substituted C _6-14 aryl-carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), optionally substituted C _7-16 aryl Alkylcarbonyl (for example, phenylacetyl, 3-phenylpropanoyl, etc.), optionally substituted 5 to 7 membered heterocyclic carbonyl containing, in addition to carbon atoms, 1 to 7 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms (for example, nicotinoyl, isonicotinoyl, thienyl, furoyl, morphinyl, thiomorphinyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), optionally esterified carboxy, optionally substituted carbamoyl, optionally substituted C _1-6 alkylsulfonyl (for example, methanesulfonyl acyl, ethylsulfinyl, etc.), optionally substituted C _1-6 alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl, etc.), optionally substituted C _6-14 arylsulfinyl (such as , benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.), optionally substituted C _6-14 arylsulfinyl (for example, benzenesulfinyl, 1-naphthalenesulfinyl, 2-naphthalenesulfinyl Sulfinyl, etc.), optionally substituted C _1-6 alkylcarbonyloxy (for example, acetate, propionate, etc.), optionally substituted C _6-14 aryl-carbonyloxy (for example, benzoyl , naphthoyl, etc.), optionally substituted C _1-6 alkoxy-carbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy group, etc.), optionally substituted mono-C _1-6 alkylcarbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), optionally substituted di-C _{1 -6} alkylcarbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), optionally substituted mono- or di-C _6-14 arylcarbamoyloxy ( For example, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), optionally substituted heterocyclic group, sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, or these A combination of 2 or more (for example, 2 or 3) of substituents, etc. (substituent A). The number of substituents is not particularly limited, and the ring may have 1 to 5, preferably 1 to 3, substituents at substitutable positions. When there are 2 or more substituents, each substituent may be the same or different.

The "optionally esterified carboxyl" used in substituent A includes, for example, optionally substituted C _1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxycarbonyl, etc.), optionally substituted C _6-14 aryloxy-carbonyl (for example, phenoxycarbonyl, etc.), optionally substituted C _7-16 aralkoxy-carbonyl (for example, benzyloxycarbonyl, benzene Ethoxycarbonyl, etc.) etc.

"C _1-6 alkyl" in "optionally substituted C _1-6 alkyl" used in substituent A includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl Base, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The "C _2-6 alkenyl" in the "optionally substituted C _2-6 alkenyl" used in substituent A includes, for example, vinyl, propenyl, isopropenyl, 2-butene-1 -yl, 4-penten-1-yl, 5-hexen-1-yl, etc.

The "C _2-6 alkynyl group" in the "optionally substituted C _2-6 alkynyl group" used in substituent A includes, for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.

The "C _3-8 cycloalkyl" in the "optionally substituted C _3-8 cycloalkyl" used in the substituent A includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The "C _6-14 aryl" in the "optionally substituted C _6-14 aryl" used in substituent A includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl , 3-biphenyl, 4-biphenyl, 2-anthracenyl, etc.

The "C _7-16 aralkyl group" in the "optionally substituted C _7-16 aralkyl group" used in substituent A includes, for example, benzyl, phenethyl, benzhydryl, 1-naphthoyl Base, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl (2-biphenylylmethyl), 3- Biphenylmethyl, 4-biphenylmethyl), etc.

"C _1-6 alkoxy" in "optionally substituted C _1-6 alkoxy" used in substituent A includes, for example, methoxy, ethoxy, propoxy, isopropoxy , butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.

"C _6-14 aryloxy" in "optionally substituted C _6-14 aryloxy" used in substituent A includes, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc. .

The "C _7-16 aralkoxy" in the "optionally substituted C _7-16 aralkoxy" used in the substituent A includes, for example, benzyloxy, phenethoxy and the like.

"C _1-6 alkylthio" in "optionally substituted C _1-6 alkylthio" used in substituent A includes, for example, methylthio, ethylthio, propylthio, isopropylthio , Butylthio, sec-butylthio, tert-butylthio, etc.

The "C _6-14 arylthio" in the "optionally substituted C _6-14 arylthio" used in the substituent A includes, for example, phenylthio, 1-naphthylthio, 2-naphthylthio, etc. .

The "C _7-16 aralkylthio" in the "optionally substituted C _7-16 aralkylthio" used in the substituent A includes, for example, benzylthio, phenethylthio and the like.

In substituent A, for "C _1-6 alkoxy-carbonyl", "C _1-6 alkyl", "C _2-6 alkenyl", "C _2-6 alkynyl", "C _{1 -6} alkoxy", "C _1-6 alkylthio", "C _1-6 alkyl-amino", "C _2-6 alkenyl-amino", "C _2-6 alkynylamino", "C _1-6 alkoxyamino", "C _1-6 alkylcarbonyl", "C _1-6 alkylsulfonyl", "C _1-6 alkylsulfinyl", "C _1-6 alkane Carbonylamino", "C _1-6 Alkoxy-carbonylamino", "C _1-6 Alkylsulfonylamino", "C _1-6 Alkylcarbonyloxy", "C _1-6 Alkoxy The substituents used for "-carbonyloxy", "mono-C _1-6 alkylcarbamoyloxy" and "di-C _1-6 alkylcarbamoyloxy" include 1 to 5 selected from the following A substituent, the group such as halogen (such as fluorine atom, chlorine atom, bromine atom, iodine atom), carbonyl, hydroxyl, amino, mono or di-C _1-6 alkylamino, mono or di-C _{6- 14} Arylamino, C _3-8 cycloalkyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, the above-mentioned optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl (for example methylcarbamoyl, ethylamino formyl, etc.), di-C _1-6 alkylcarbamoyl (such as dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), mono or di-C _6-14 Arylcarbamoyl (such as phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.) and mono- or di-5 to 7-membered heterocyclic carbamoyl (such as 2-pyridyl carbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), the mono- or di-5 to 7-membered heterocycle The carbamoyl group contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms.

In substituent A, for "C _6-14 aryloxy-carbonyl", "C _7-16 aralkyloxy-carbonyl", "C _3-8 cycloalkyl", "C _6-14 aryl" , "C _7-16 aralkyl", "C _6-14 aryloxy", "C _7-16 aralkyloxy", "C _6-14 arylthio", "C _7-16 aralkylthio group", "C _3-8 cycloalkyl-amino", "C _6-14 arylamino", "C _3-8 cycloalkylcarbonyl", ""C _6-14 aryl-carbonyl", "C _7-16 aralkylcarbonyl", "5 to 7 membered heterocyclic carbonyl containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms 1 or 2 of ", "C _6-14 arylsulfonyl", "C _6-14 arylsulfinyl", "C _3-8 cycloalkanoylamino", "C _6-14 aryl- Carbonylamino", "C _6-14 arylsulfonylamino", "C _6-14 aryl-carboxy" and "mono- or di-C _6-14 arylcarbamoyloxy" include selected 1 to 5 substituents selected from the following, such as a halogen atom, a hydroxyl group, a carbonyl group, a nitro group, a cyano group, the above-mentioned optionally substituted C _1-6 alkyl, the above-mentioned optionally substituted C _{2- 6} alkenyl, the above-mentioned optionally substituted C _2-6 alkynyl, the above-mentioned optionally substituted C _3-8 cycloalkyl, the above-mentioned optionally substituted C _1-6 alkoxy, the above-mentioned optionally Substituted C _1-6 alkylthio, the above optionally substituted C _1-6 alkylsulfinyl, the above optionally substituted C _1-6 alkylsulfonyl, the above optionally esterified carboxy , carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl, di-C _1-6 alkylcarbamoyl, mono or di-C _6-14 arylcarbamoyl and mono Or a two-5 to 7-membered heterocyclic carbamoyl group, etc., the single or two-5 to 7-membered heterocyclic carbamoyl group contains 1 to 4 heteroatoms in addition to carbon atoms, and the heteroatoms are selected from 1 or 2 of nitrogen, sulfur and oxygen atoms.

The "optionally substituted heterocyclic group" used in the substituent A includes, for example, a 5 to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group containing, in addition to carbon atoms In addition, it also contains 1 to 4 heteroatoms, the heteroatoms are selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, and the 5 to 14 membered heterocyclic groups can be optionally substituted by the following groups, the Said group is a halogen atom, hydroxyl, carbonyl, nitro, cyano, the above-mentioned optionally substituted C _1-6 alkyl, the above-mentioned optionally substituted C _2-6 alkenyl, the above-mentioned optionally substituted C _2-6 alkynyl, the above optionally substituted C _3-8 cycloalkyl, the above optionally substituted C _6-14 aryl, the above optionally substituted C _1-6 alkoxy, the above Optionally substituted C _1-6 alkylthio, above-mentioned optionally substituted C _6-14 arylthio, above-mentioned optionally substituted C _7-16 aralkylthio, above-mentioned optionally substituted C _{1- 6} alkylsulfinyl, the above-mentioned optionally substituted C _6-14 arylsulfinyl, the above-mentioned optionally substituted C _1-6 alkylsulfinyl, the above-mentioned optionally substituted C _6-14 aryl Sulfonyl, the above-mentioned optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl, di-lower alkylcarbamoyl, mono or di-C _{6 -14} arylcarbamoyl, mono or di-5 or 7-membered heterocyclic carbamoyl, etc., the mono- or di-5 or 7-membered heterocyclic carbamoyl also contains 1 to 4 carbon atoms Heteroatom, the heteroatom is selected from 1 or 2 kinds of nitrogen, sulfur and oxygen atoms;, preferably (i) 5 to 14 yuan (preferably 5 to 10 yuan) aromatic heterocyclic group, (ii) 5 to a 10-membered non-aromatic heterocyclic group, or (iii) a monovalent group obtained by connecting an optional hydrogen atom in a 7- to 10-membered heterocyclic ring, more preferably a 5-membered aromatic heterocyclic group. Specifically used aromatic heterocyclic groups such as thienyl (such as 2-thienyl, 3-thienyl), furyl (such as 2-furyl, 3-furyl), pyridyl (such as 2-pyridyl, 3- Pyridyl, 4-pyridyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (such as 2-oxazolyl, 4-oxazolyl), quinolinyl (e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 8-quinolinyl), isoquinolinyl (e.g. 1-isoquinolinyl, 3-isoquinolinyl Linyl, 4-isoquinolyl, 5-isoquinolyl), pyrazinyl, pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (such as 1-pyrrolyl, 2-pyrrolyl , 3-pyrrolyl), imidazolyl (such as 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (such as 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl) , pyridazinyl (eg 3-pyridazinyl, 4-pyridazinyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl), indolyl (eg 1-indolyl, 2-indolyl, 3-indolyl), 2-benzothiazolyl, benzo[b]thienyl, (e.g. 2-benzo[b]thienyl, 3-benzo [b]thienyl), benzo[b]furyl (such as 2-benzo[b]furyl, 3-benzo[b]furyl), etc., specifically used non-aromatic heterocyclic groups such as pyrrolidine (for example 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (for example 2-oxazolidinyl), imidazolinyl (for example 1-imidazolinyl, 2-imidazole Linyl, 4-imidazolinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g. 1-piperazinyl , 2-piperazinyl), morpholino, thiomorpholino, etc.

The "optionally substituted carbamoyl" used in the substituent A includes the above-mentioned optionally substituted C _1-6 alkyl, the above-mentioned optionally substituted C _2-6 alkenyl, the above-mentioned optionally substituted Optionally substituted carbamoyl groups such as C _2-6 alkynyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-14 aryl, optionally substituted heterocyclic group, specific examples are amino Formyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl (such as methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkylcarbamoyl (such as di Methylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.); C _1-6 alkyl (C _1-6 alkoxy) carbamoyl (such as methyl (methoxy) Carbamoyl, ethyl(methoxy)carbamoyl), mono- or di-C _6-14 arylcarbamoyl (e.g. phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylamino formyl, etc.), a single or two 5- to 7-membered heterocyclic carbamoyl group, the single or two 5- to 7-membered heterocyclic carbamoyl group contains 1 to 4 heteroatoms in addition to carbon atoms, and the heterocyclic The atom is selected from 1 or 2 kinds of nitrogen, sulfur and oxygen atoms, (such as 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.); 5- to 7-membered cyclic carbamoyl (eg, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, hexamethyleneiminocarbonyl) and the like.

"Optionally substituted amino" as used in substituent A includes amino optionally substituted with 1 or 2 groups selected from the group consisting of optionally substituted C _1-6 alkyl , the above-mentioned optionally substituted C _2-6 alkenyl, the above-mentioned optionally substituted C _2-6 alkynyl, the above-mentioned optionally substituted C _3-8 cycloalkyl, the above-mentioned optionally substituted C _{6 -14} aryl, the above optionally substituted C _1-6 alkoxy, formyl, the above optionally substituted C _1-6 alkylcarbonyl, the above optionally substituted C _3-8 cycloalkylcarbonyl , the above-mentioned optionally substituted C _6-14 aryl-carbonyl, the above-mentioned optionally substituted C _1-6 alkoxy-carbonyl, the above-mentioned optionally substituted C _1-6 alkylsulfonyl, optionally substituted C _6-14 arylsulfonyl, etc.

More preferably, for "C _6-12 aromatic hydrocarbon group", "5 to 14 membered aromatic heterocyclic group, said 5 to 14 membered aromatic heterocyclic group consists of 1 to 7 carbon atoms and is selected from nitrogen, oxygen Composed of heteroatoms with sulfur atoms", "C _8-14 aromatic fused heterocyclic group", "5 to 14 membered aromatic fused heterocyclic group, the 5 to 14 membered aromatic fused heterocyclic group consists of 3 to 11 Substituents consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur atoms", "non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms" and "non-aromatic heterocyclic groups with no more than 7 carbon atoms" Yes, halogen atom, hydroxyl, C _1-6 alkoxy, optionally halogenated C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, amino, nitro, cyano, etc.

Examples of R ⁴ include:

(1) "C _1-4 alkyl, said C _1-4 alkyl has an optionally substituted C _6-12 aromatic hydrocarbon group" such as benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4- Fluorobenzyl, 4-chlorobenzyl, 3,4-difluorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3-tri Fluoromethylbenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4-cyanobenzyl, phenethyl, etc.;

(2) "C _1-4 alkyl having an optionally substituted 5- to 14- _membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom, the heteroatom selected from nitrogen, oxygen and sulfur atoms" such as 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 4-thiazolylmethyl Base etc.;

(3) "C _1-4 alkyl, said C _1-4 alkyl has an optionally substituted C _8-14 aromatic condensed ring group" such as 1-naphthylmethyl, 2-naphthylmethyl, indene-2 - methyl, etc.;

(4) "C _1-4 alkyl, said C _1-4 alkyl has a 5 to 14 membered aromatic condensed heterocyclic group consisting of 3 to 11 carbon atoms and a heteroatom selected from nitrogen , oxygen and sulfur atoms" such as 3-indolylmethyl, 1-formylindol-3-ylmethyl, 3-benzo[b]thienylmethyl, 2-quinolylmethyl, etc.;

(5) "C _1-4 alkyl, said C _1-4 alkyl having an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms" such as cyclohexylmethyl, cyclopentylmethyl, indene Full-2-ylmethyl, etc.;

(6) "C _1-4 alkyl, said C _1-4 alkyl has an optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms" such as 4-piperidinylmethyl, tetrahydrofurfuryl Base, tetrahydrofuran-2-yl, tetrahydropyran-3-yl, indolin (indolin)-3-yl, etc., preferably benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl Base, 4-hydroxybenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4-cyanobenzyl, 3-trifluoromethylbenzyl , 3,4-dichlorobenzyl, 3,4-difluorobenzyl, pentafluorobenzyl, 3-pyridylmethyl, 4-pyridylmethyl, 3-indolylmethyl, 1-formyl Indol-3-ylmethyl, 3-benzo[b]thienylmethyl, 2-quinolylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, cyclohexylmethyl, phenethyl, etc. , more preferably benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4-cyanobenzyl, 3-trifluoromethylbenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, pentafluorobenzyl, 3-pyridine ylmethyl, 4-pyridylmethyl, 3-indolylmethyl, 3-benzo[b]thienylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, cyclohexylmethyl, etc.

Q ¹ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the group consisting of:

(1) Optionally substituted C _6-12 aromatic hydrocarbon groups;

(2) An optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur atoms;

(3) optionally substituted C _8-14 aromatic fused ring groups;

(4) An optionally substituted 5- to 14-membered aromatic condensed heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur atom;

(5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms; and

(6) an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms; and the same substituents as used for R ⁴ .

Examples of Q ¹ include:

(1) "C _1-4 alkyl, said C _1-4 alkyl has an optionally substituted C _6-12 aromatic hydrocarbon group" such as benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4- Fluorobenzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-tri Fluoromethylbenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4-cyanobenzyl, phenethyl, etc.;

(2) "C _1-4 alkyl having an optionally substituted 5- to 14- _membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom, the heteroatom selected from nitrogen, oxygen and sulfur atoms" such as 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 4-thiazolylmethyl Base etc.;

(3) "C _1-4 alkyl, said C _1-4 alkyl has an optionally substituted C _8-14 aromatic condensed ring group" such as 1-naphthylmethyl, 2-naphthylmethyl, indene-2 - methyl, etc.;

(4) "C _1-4 alkyl, said C _1-4 alkyl has a 5 to 14 membered aromatic condensed heterocyclic group consisting of 3 to 11 carbon atoms and a heteroatom selected from nitrogen , oxygen and sulfur atoms" such as 3-indolylmethyl, 1-formylindol-3-ylmethyl, 3-benzo[b]thienylmethyl, 2-quinolylmethyl, etc.;

(5) "C _1-4 alkyl, said C _1-4 alkyl having an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms" such as cyclohexylmethyl, cyclopentylmethyl, indene Full-2-ylmethyl, etc.;

(6) "C _1-4 alkyl, said C _1-4 alkyl has an optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms" such as 4-piperidinylmethyl, tetrahydrofurfuryl Base, tetrahydrofuran-2-yl, tetrahydropyran-3-yl, indolin-3-yl, etc., preferably cyclohexylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4- Methoxybenzyl, pentafluorobenzyl, 2-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolylmethyl, 2-thienylmethyl group, etc., more preferably benzyl, 4-fluorobenzyl, cyclohexylmethyl and the like.

Q ² represents (1) CH ₂ , which may _{be optionally substituted by optionally substituted C 1-4 alkyl} having a substituent selected from carbamoyl _and hydroxyl, ( ₂ ) NH which may be optionally substituted with optionally substituted C _1-4 alkyl having a substituent selected from carbamoyl and hydroxy, or (3)O.

Examples of "C _1-4 alkyl" are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

Preferably, Q ² is CH ₂ , CH(CH ₃ ), CH(CH ₂ OH), NH or the like.

Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH ₂ - or -CH═CH-, which may be optionally substituted by C _1-6 alkyl.

Examples of "C _1-6 alkyl" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl base, hexyl, etc.

Preferably, Y is a group represented by the following formula: -CONH-, -CSNH-, -NHCO-, -CH ₂ NH-, -CH ₂ O-, -COO- or -CSO- (more preferably A group represented by the following formula: -CONH-, -CSNH-, -NHCO- or -CH ₂ NH-).

^Z represents a hydrogen atom, O or S, preferably O or S;

Wherein, when Z ⁹ represents a hydrogen atom, the structure of the part shown by >C=Z ⁹ represents the structure of >CH ₂ .

P and P' can be the same or different, and each can form a ring through the combination of P and P', or P and ^Q1 , representing:

(1) Hydrogen atom;

(2) Optional amino acid residues that are continuously or discontinuously combined with the C-terminus of the 1-48 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1;

(3) A group represented by the following formula:

J ¹ -J ² -C(J ³ )(Q ³ )Y ¹ C(J ⁴ )(Q ⁴ )y ² C(J ⁵ )(Q ⁵ )Y ³ C(J ⁶ )(Q ⁶ )C( =Z ¹⁰ )-(wherein, the meaning of each symbol is the same as above);

(4) A group represented by the following formula:

-J ¹ -J ² -C(J ⁷ )(Q ⁷ )Y ² C(J ⁸ )(Q ⁸ )Y ³ C(J ⁹ )(Q ⁹ )C(=Z ¹⁰ )-(wherein, each symbol has the same meaning as above);

(5) A group represented by the following formula:

J ¹ -J ² -C(J ¹⁰ )(Q ¹⁰ )Y ³ C(J ¹¹ )(Q ¹¹ )C(=Z ¹⁰ )-(wherein, the meanings of the symbols are the same as above);

(6) A group represented by the following formula:

J ¹ -J ² -C(J ¹² )(Q ¹² )C(=Z ¹⁰ )- (wherein, the meanings of the symbols are the same as above); or,

(7) A group represented by the following formula:

J ^1- (wherein, the meaning of J ¹ is the same as above).

The "optional amino acid residues that are continuously or discontinuously combined with the C-terminus of the 1-48 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1" include:

(1)Asn-

(2) Trp Asn-,

(3) Asn Trp Asn-,

(4) Tyr Asn Trp Asn-,

(5) Asn Tyr Asn Trp Asn-,

(6) Pro Asn Tyr Asn Trp Asn-,

(7) Leu Pro Asn Tyr Asn Trp Asn-,

(8)Asp Leu Pro Asn Tyr Asn Trp Asn-,

(9)Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(10) Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(11) Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(12) Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(13) Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(14) Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(15) Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(16) Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(17) Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn TrpAsn-,

(18) Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr AsnTrp Asn-,

(19) Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn TyrAsn Trp Asn-,

(20) Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn TyrAsn Trp Asn-,

(21) Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro AsnTyr Asn Trp Asn-,

(22) Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu ProAsn Tyr Asn Trp Asn-,

(23) Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp LeuPro Asn Tyr Asn Trp Asn-,

(24) Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys AspLeu Pro Asn Tyr Asn Trp Asn-,

(25) Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu LysAsp Leu Pro Ash Tyr Asn Trp Asn-,

(26) His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg GluLys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(27) Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln ArgGlu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(28) Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val GlnArg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-

(29) Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu ValGln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(30) Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val LeuVal Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(31) Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala ValLeu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(32) Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly AlaVal Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(33) Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln GlyAla Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(34) Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro GlnGly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(35) Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala ProGln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(36) Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro AlaPro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn TrpAsh-,

(37) Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile ProAla Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn TrpAsn-,

(38) Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln IlePro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr AsnTrp Asn-,

(39) Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg GlnIle Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn TyrAsn Trp Asn-,

(40) Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser ArgGln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro AsnTyr Ash Trp Asn-,

(41) Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His SerArg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu ProAsn Tyr Asn Trp Asn-,

(42) Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro HisSer Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp LeuPro Asn Tyr Asn Trp Asn-,

(43) Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala ProHis Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys AspLeu Pro Asn Tyr Asn- Trp Asn-

(44) Ser Pro Pro Pro Glu Ser Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser AlaPro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu LysAsp Leu Pro Asn Tyr Asn- Trp

(45) Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu SerAla Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg GluLys Asp Leu Pro Asn - Trp Asn Asn - Trp Asn Asn

(46) Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly LeuSer Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln ArgGlu Lys Asp Leu Pro Asn Trr

(47) Thr Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro GlyLeu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val GlnArg Glu Lys As Asp Leu r Pro Asn，

(48) Gly Thr Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln ProGly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu ValGln Arg As p Asp Aspn Leu r Pro wait.

^J represents (a) a hydrogen atom, or (b) (i) C _1-15 acyl, (ii) C _1-15 alkyl, (iii) C _6-14 aryl, (iv) carbamoyl, ( v) carboxy, (vi) sulfinate, (vii) amidino, (viii) glyoxyl or (ix) amino, these groups may be optionally substituted with substituents containing optionally substituted cyclic groups.

The "cyclic group" used includes, for example, "optionally substituted aromatic hydrocarbon group", "optionally substituted aromatic heterocyclic group", "optionally substituted aromatic condensed ring group", "optionally substituted aromatic Fused heterocyclic group", "optionally substituted non-aromatic cyclic hydrocarbon group", "optionally substituted non-aromatic heterocyclic group", etc., and as "aromatic hydrocarbon group", "aromatic heterocyclic group", "aromatic "Aromatic fused ring group" and "aromatic fused heterocyclic group" use the same groups as above.

The "non-aromatic cyclic hydrocarbon group" used includes, for example, C _3-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The "non-aromatic heterocyclic group" used includes, for example, a 5- or 10-membered non-aromatic heterocyclic group containing, in addition to 1 to 7 carbon atoms, 1 to 7 carbon atoms. 4 heteroatoms, the heteroatoms are selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, the 5 to 10 membered non-aromatic heterocyclic group such as pyrrolidinyl (such as 1-pyrrolidinyl, 2-pyrrole Alkyl, 3-pyrrolidinyl), oxazolidinyl (e.g. 2-oxazolidinyl), imidazolinyl (e.g. 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidine Base (such as 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl), piperazinyl (such as 1-piperazinyl, 2-piperazinyl), morpholino, Thiomorpholino, etc.

The substituents which may optionally be present on the "ring group" include the same substituents used for the substituent A above.

The "C _1-15 acyl group" used includes, for example, formyl, C _1-14 alkylcarbonyl (for example, C _1-6 alkylcarbonyl, such as acetyl, propionyl, pivaloyl, etc.) and the like.

Examples of "C _1-15 alkyl" used include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl Base, hexyl, heptyl, octyl, nonyl, decyl, etc.

Examples of the "C _6-14 aryl" used include phenyl, 1-naphthyl, 2-naphthyl, biphenyl and the like.

(1) C _1-15 acyl, said C _1-15 acyl may be optionally substituted by a ring-containing substituent, including (i) formyl, (ii) C _1-14 alkylcarbonyl (such as C _{1-14 6} alkylcarbonyl, such as acetyl, propionyl, pivaloyl, etc.), (iii) C _3-8 cycloalkylcarbonyl (such as cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methylcyclo Hexylcarbonyl, etc.), (iv) C _3-8 cycloalkyl-C _1-6 alkylcarbonyl (such as cyclopropylacetyl, cyclopentylacetyl, cyclohexylacetyl, etc.), (v) C _{6- 14} aryl-carbonyl (such as benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _6-14 aralkylcarbonyl (such as phenylacetyl, 3-phenylpropionyl, etc.), ( vi) 5- to 7-membered monocyclic heterocyclic carbonyl containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms 1 or 2 of these, (such as nicotinoyl, isonicotinoyl, thienyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl etc.) (vii) 5 to 7 membered monocyclic heterocycle-C _1-6 alkylcarbonyl, said 5 to 7 membered monocyclic heterocycle-C _1-6 alkylcarbonyl containing 1 to 7 carbon atoms in addition to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (for example 3-pyridylacetyl, 4-pyridylacetyl, 2-thienylacetyl, 2-furan acetyl, morpholinoacetyl, thiomorpholinoacetyl, piperidin-2-ylacetyl, pyrrolidin-2-ylacetyl, etc.), (viii) 5 to 14 members (preferably 5 to 10-membered) bicyclic or tricyclic aromatic heterocyclic carbonyl containing, in addition to 3 to 11 carbon atoms, 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms 2 types, (e.g. 2-indolecarbonyl, 3-indolecarbonyl, 2-quinolylcarbonyl, 1-isoquinolylcarbonyl, 2-benzo[b]thienylcarbonyl, 2-benzo[b] furylcarbonyl, etc.), (ix) 5 to 14 membered (preferably 5 to 10 membered) bicyclic or tricyclic aromatic heterocyclic-C _1-6 alkylcarbonyl, except that it contains 3 to 11 carbon atoms Also contain 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (e.g. 2-indoleacetyl, 3-indoleacetyl, 2-quinolylacetyl group, 1-isoquinolylacetyl group, 2-benzo[b]thienylacetyl group, 2-benzo[b]furylacetyl group, etc.), preferably acetyl group, 2-indolecarbonyl group, 3 -indolecarbonyl, 3-indoleacetyl, 3-indolepropionyl, 2-indolinecarbonyl, 3-phenylpropionyl, diphenylacetyl, 2-pyridinecarbonyl, 3-pyridinecarbonyl, 4 -pyridinecarbonyl, 1-pyridinioacetyl, 2-pyridineacetyl, 3-pyridineacetyl, 4-pyridineacetyl, 3-(1-pyridinio)propionyl, 3-(pyridin-2-yl)propionyl, 3-(pyridin-3-yl)propionyl, 3-(pyridin-4-yl)propionyl, 4-imidazoleacetyl, cyclohexanecarbonyl, 1-piper Pyridine acetyl, 1-methyl-1-piperidinioacetyl (piperidinioacetyl), 4-piperidine carbonyl, 2-pyrimidine carbonyl, 4-pyrimidine carbonyl, 5-pyrimidine carbonyl, 2-pyrimidine acetyl, 4- Pyrimidineacetyl, 5-pyrimidineacetyl, 3-(pyrimidin-2-yl)propionyl, 3-(pyrimidin-4-yl)propionyl, 3-(pyrimidin-5-yl)propionyl, butyryl, hexyl acyl, octanoyl, D-glucuronyl, amino-(4-hydroxyphenyl)acetyl) and the like.

(2) The C _1-15 alkyl used, which may be optionally substituted by a ring-containing substituent, including, for example _, (i) mono- or di-C _1-15 alkyl (e.g. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl), (ii) mono or di-C _3-8 cycloalkyl (such as cyclopropyl, cyclopentyl, etc.), (iii) mono or di-C _3-8 cycloalkyl-C _1-7 alkane (such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylethyl, etc.), (iv) mono- or di-C _7-15 aralkyl (such as benzyl, phenethyl, etc.), (v) Mono- or two-5 to 7-membered monocyclic heterocycle-C _1-6 alkyl, which contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms 1 or 2 kinds, (such as 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, furfuryl, etc.), (vi) mono or di-5 to 14 members (preferably 5 to 10 member) bicyclic or tricyclic aromatic heterocyclic ring-C _1-6 alkyl, which, in addition to containing 3 to 11 carbon atoms, also contains 1 to 4 heteroatoms, the heteroatoms are selected from nitrogen, sulfur and One or two of the oxygen atoms, (e.g. 2-indolylmethyl, 3-indolylmethyl, 3-(indol-3-yl)propyl, 2-quinolylmethyl, 1-isoquinolyl phenylmethyl, 2-benzo[b]thienylmethyl, 2-benzo[b]furylmethyl, etc.), preferably methyl, ethyl, benzyl, 3-(indole-3 - base) propyl etc.

(3) The C _6-14 aryl used, the C _6-14 aryl may be optionally substituted by a ring-containing substituent, including, for example, a C _6-14 aryl (such as phenyl, naphthyl, biphenyl group), the C _6-14 aryl group may be optionally substituted by (i) C _6-14 carbocyclic group (such as cycloalkyl, phenyl, 1-naphthyl, 2 - naphthyl, etc.), (ii) 5 to 7 membered monocyclic heterocyclic group, said 5 to 7 membered monocyclic heterocyclic group contains 1 to 4 heteroatoms in addition to carbon atoms, said heteroatoms are selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (e.g. 3-pyridyl, 2-thienyl, etc.), (iii) 5 to 14 membered (preferably 5 to 10 membered) bicyclic or tricyclic aromatic A heterocyclic group containing, in addition to 3 to 11 carbon atoms, 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (for example 2-indolyl , 3-indolyl, 2-quinolyl, 1-isoquinolyl, 2-benzo[b]thienyl, 2-benzo[b]furyl, etc.) and the like.

(4) Optionally substituted carbamoyl used, which may be optionally substituted by a ring-containing substituent, including, for example, (i) carbamoyl, (ii) mono- or di-C _1-15 alkylaminomethyl Acyl (e.g. methylcarbamoyl, ethylcarbamoyl), (iii) mono- or di-C _3-8 cycloalkyl-carbamoyl (e.g. cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, etc.), (iv) mono- or di-C _3-8 cycloalkyl-C _1-6 alkyl-carbamoyl (such as cyclopropylmethylcarbamoyl, cyclopentylmethylamino formyl, 2-cyclohexylethylcarbamoyl, etc.), (v) mono or di-C _6-14 aryl-carbamoyl (such as phenylcarbamoyl, etc.), mono or di-C _6-14 Aralkyl-carbamoyl (e.g. benzylcarbamoyl, phenethylcarbamoyl, etc.), (vi) mono- or di-5 to 7-membered monocyclic heterocyclic carbamoyl, which contains other than carbon atoms Also contain 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (e.g. 3-pyridinecarbamoyl, 2-thiophenecarbamoyl, piperidin-3-yl carbamoyl, etc.), (vii) mono- or di-5 to 7-membered monocyclic heterocycle-C _1-6 alkylcarbamoyl, which contains 1 to 4 heteroatoms in addition to carbon atoms, said The heteroatom is selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (for example, 3-pyridylmethylcarbamoyl, 2-(pyridin-2-yl)ethylcarbamoyl, 2-(piperidine -1-yl) ethylcarbamoyl, etc.), (viii) mono or di-5 to 14 membered (preferably 5 to 10 membered) bicyclic or tricyclic aromatic heterocyclic carbamoyl, which contains 3 to In addition to 11 carbon atoms, 1 to 4 heteroatoms are selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (for example, 4-indolecarbamoyl, 5-indolecarbamoyl Acyl, 3-quinolylcarbamoyl, 5-quinolylcarbamoyl, etc.), (ix) mono or di-5 to 14 membered (preferably 5 to 10 membered) bicyclic or tricyclic aromatic heterocycle -C _1-6 alkylcarbonyl, which contains, in addition to 3 to 11 carbon atoms, 1 to 4 heteroatoms selected from 1 or 2 of nitrogen, sulfur and oxygen atoms, (for example benzimidazol-2-ylmethylcarbamoyl, 2-(indol-3-yl)ethylcarbamoyl, etc.), (x) 5- to 7-membered cyclic carbamoyl (e.g. 1-pyrrolidinyl carbonyl, 1-piperidinylcarbonyl, hexamethyleneiminocarbonyl, etc.), (xi) C _1-15 acylcarbamoyl (here the C _1-15 acyl and "used C _1-15 acyl, the The meaning of "C _1-15 acyl" in "C _1-15 acyl can be optionally substituted by a ring-containing substituent" has the same meaning), (xii) C _1-15 alkylaminocarbamoyl (herein C _{1 -15} alkyl has the same meaning as "C _1-15 alkyl" in "C _1-15 alkyl, said C _1-15 alkyl may be optionally substituted by a ring-containing substituent", (xiii) C _6-14 arylaminocarbamoyl (herein C _6-14 aryl and "C _6-14 aryl, the C _6-14 aryl may be optionally substituted by a ring-containing substituent" have the same meaning), etc., preferably 2-(indol-3-yl)ethylcarbamoyl and the like.

(5) The carboxyl group used, which may be optionally substituted by a ring-containing substituent, includes, for example, (i) C _1-15 alkoxycarbonyl (herein C _1-15 alkyl and "C _1-15 alk The C _1-15 alkyl group can be optionally substituted by a ring-containing substituent" in "C _1-15 alkyl" has the same meaning, such as tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorene methoxycarbonyl), (ii) C _6-14 aryloxycarbonyl (here C _6-14 aryl and "C _6-14 aryl, the C _6-14 aryl can optionally be ring-containing The "C _6-14 aryl" in "Substitution" has the same meaning, such as phenoxycarbonyl) and the like.

(6) The sulfinic acid group used, which may be optionally substituted by a ring-containing substituent, including, for example, (i) C _1-15 alkylsulfonyl (herein C _1-15 alkyl The same meaning as "C _1-15 alkyl" in "C _{1-15 alkyl, said C 1-15 alkyl} may be optionally substituted by a ring-containing substituent", such as benzylsulfonyl), (ii) C _6-14 arylsulfonyl (here C _6-14 aryl and "C _6-14 aryl, the C _6-14 aryl may be optionally substituted by a ring-containing substituent""C _6-14 aryl" has the same meaning, for example, tosyl) and the like.

(7) amidino used, which may be optionally substituted by a ring-containing substituent, including, for example, (i) amidino, (ii) C _1-15 alkyl amidino (where C _1-15 Alkyl has the same meaning as the "C _1-15 group" in "C _1-15 alkyl, said C _1-15 alkyl may be optionally substituted by a ring-containing substituent", such as N-methylamidino ), (iii) C _1-15 acyl amidino (herein C _1-15 acyl and "C _1-15 acyl, the C _1-15 acyl may be optionally substituted by a ring-containing substituent" in "C _1-15 acyl" has the same meaning, such as N-acetylamidino) and the like.

(8) The glyoxyl group used, which may be optionally substituted by a ring-containing substituent, including, for example, (i) C _1-15 alkyl oxalyl (where C _1-15 alkyl is combined with "C _1-15 alkyl group, the C _1-15 alkyl group can be optionally substituted by a ring-containing substituent" in "C _1-15 alkyl group" has the same meaning, for example, ethyl oxalyl), (ii) C _6-14 aryl oxalyl (herein C _6-14 aryl and "C _6-14 aryl, the C _6-14 aryl may be optionally substituted by a ring-containing substituent" in "C _{6 -14} aryl" has the same meaning, such as phenyl oxalyl) and the like.

(9) The amino group used, which may be optionally substituted by a ring-containing substituent, including, for example, (i) C _1-15 alkylamino (where C _1-15 alkyl and "C _1-15 alkane The C _1-15 alkyl group may be optionally substituted by a ring-containing substituent" has the same meaning as "C _1-15 alkyl".

Among the above, J ^is preferably a hydrogen atom, formyl, acetyl, 3-indolecarbonyl, 3-(indol-3-yl) propionyl, 3-phenylpropionyl, diphenylacetyl, 3-( Pyridin-3-yl)propionyl, 4-imidazoleacetyl, cyclohexanecarbonyl, 1-piperidineacetyl, 1-methyl-1-piperidinoacetyl (piperdinioacetyl), 4-piperidinecarbonyl, Hexanoyl, amino-(4-hydroxyphenyl)acetyl, D-glucuronyl, 2-(indol-3-yl)ethylcarbamoyl, tert-butoxycarbonyl, 9-fluorenylmethoxy Carbonyl, amidino, 4-guanidinomethylbenzoyl, benzoyl, 3-indoleacetyl, benzyloxycarbonyl, tosyl, phenyl, benzyl, phenethyl, 3-pyridinecarbonyl, 2-pyridinecarbonyl, 4-pyridinecarbonyl, propionyl, isobutyryl, phenylacetyl, 2-methylnicotinoyl, 5-methylnicotinoyl, 6-methylnicotinoyl, pyrazinecarbonyl, cyclopropanecarbonyl, Trifluoroacetyl, (R)-3-hydroxy-2-methylpropionyl, 2-hydroxyisobutyryl, 3-furancarbonyl, pyrrole-2-carbonyl, 4-imidazolecarbonyl, 6-hydroxynicotinoyl, 6 -Chloronicotinoyl, 6-(trifluoromethyl)nicotinoyl, dimethylcarbamoyl, 1-azetidinecarbonyl, 2-azetidinecarbonyl, 4-aminobenzoyl, 4- Aminomethylbenzoyl, pyrrole-3-carbonyl, pyrimidine-4-carbonyl, pyrimidine-2-carbonyl, pyridazine-4-carbonyl, 6-aminocaproyl, glycyl, glycylglycyl, glycyl Aminoylglycylglycyl, alanylalanylalanyl, alanylalanylalanylalanyl, acetylglycyl, acetylglycylglycyl, acetylglycylglycyl Aminoylglycyl, Acetylalanylalanylalanyl, Acetylalanylalanylalanylalanyl, D-arginylglycyl, D-arginylglycyl Glycyl, D-Arginylglycylglycylglycyl, D-Arginylalanylalanylalanyl, D-Arginylalanylalanylalanylalanyl Acyl, Acetyl-D-Arginylglycyl, Acetyl-D-Arginylglycylglycyl, Acetyl-D-Arginylglycylglycylglycyl, Acetyl- D-Arginylalanylalanylalanyl, Acetyl-D-arginylalanylalanylalanylalanyl, cyclopropanecarbonyl, cyclopentanecarbonyl, cyclobutanecarbonyl, Cyclohexanecarbonyl, 1-naphthoyl, 2-naphthoyl, arginyl, arginyl arginyl, 6-(arginylamino)hexanoyl, 6-(D-arginylamino)hexyl Acyl, 6-(D-arginyl-D-arginylamino)hexanoyl, 6-(acetyl-D-arginylamino)hexanoyl, 6-((R)-2,3-diamino Propionylamino)caproyl, 6-(D-norleucylamino)caproyl, 3-(D-arginylamino)propionyl, 4-(D-arginylamino)butyryl, 4-( D-arginyl-D-arginylamino)butyryl, 4-(D-arginyl-D-arginyl-D-arginylamino)butyryl, 3-(4-hydroxyphenyl) Propionyl, butyryl, methyl, adipyl, pyroglutamyl, glycolyl, etc., more preferably a hydrogen atom, formyl, acetyl, propionyl, 3-indolecarbonyl, 3-(indole- 3-yl)propionyl, 3-phenylpropionyl, 3-(pyridin-3-yl)propionyl, 4-imidazoleacetyl, cyclohexanecarbonyl, hexanoyl, amino-(4-hydroxyphenyl)acetyl , 2-(indol-3-yl)ethylcarbamoyl, 9-fluorenylmethoxycarbonyl, amidino, 4-guanidinomethylbenzoyl, benzoyl, 3-indoleacetyl, benzyl Base, phenethyl, 3-pyridinecarbonyl, 2-pyridinecarbonyl, 4-pyridinecarbonyl, isobutyryl, phenylacetyl, 6-methylnicotinoyl, pyrazinecarbonyl, cyclopropanecarbonyl, trifluoroacetyl, ( R)-3-hydroxy-2-methylpropionyl, 2-hydroxyisobutyryl, 3-furancarbonyl, pyrrole-2-carbonyl, 4-imidazolecarbonyl, 6-hydroxynicotinoyl, 6-chloronicotinoyl, 6 -(trifluoromethyl)nicotinoyl, dimethylcarbamoyl, 1-azetidinecarbonyl, 4-aminobenzoyl, 4-aminomethylbenzoyl, pyrrole-3-carbonyl, pyrimidine- 4-carbonyl, pyrimidine-2-carbonyl, pyridazine-4-carbonyl, 6-aminocaproyl, cyclopropanecarbonyl, 2-naphthoyl, arginyl, 6-(arginylamino)hexanoyl, 6- (D-arginylamino)hexanoyl, 6-(D-arginyl-D-arginylamino)hexanoyl, 6-(acetyl-D-arginylamino)hexanoyl, 6-(( R)-2,3-diaminopropionylamino)caproyl, 6-(D-norleucylamino)caproyl, 3-(D-arginylamino)propionyl, 4-(D-arginine Amino)butyryl, 4-(D-arginyl-D-arginylamino)butyryl, 4-(D-arginyl-D-arginyl-D-arginylamino)butyryl, 3-(4-hydroxyphenyl)propionyl, butyryl, adipyl, pyroglutamyl, etc.

J ² represents (1) NH optionally substituted by C _1-6 alkyl, (2) CH ₂ optionally substituted by C _1-6 alkyl,

(3) O, or (4) S.

The "C _1-6 alkyl" used includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Hexyl etc.

It is preferred that ^J2 is NH.

Each of J ³ to J ¹² represents a hydrogen atom or a C _1-3 alkyl group.

The "C _1-3 alkyl" used includes methyl, ethyl, propyl, isopropyl and the like.

It is preferred that J ³ is a hydrogen atom.

It is preferred that J ⁴ is a hydrogen atom.

It is preferred that J ⁵ is a hydrogen atom.

It is preferred that J ⁶ is a hydrogen atom.

It is preferred that J ⁷ is a hydrogen atom.

It is preferred that J ⁸ is a hydrogen atom.

It is preferred that J ⁹ is a hydrogen atom.

It is preferred that J ¹⁰ is a hydrogen atom.

It is preferred that J ¹¹ is a hydrogen atom.

It is preferred that J ¹² is a hydrogen atom.

Q ³ to Q ¹² each represent a C _1-4 alkyl group or a hydrogen atom, and the C _1-4 alkyl group optionally has a substituent selected from the following:

(1) Optionally substituted C _6-12 aromatic hydrocarbon groups;

(2) An optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atoms;

(3) optionally substituted C _8-14 aromatic fused ring groups;

(4) An optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atom;

(5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms;

(6) An optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms;

(7) optionally substituted amino groups;

(8) optionally substituted guanidino;

(9) optionally substituted hydroxyl;

(10) optionally substituted carboxy;

(11) optionally substituted carbamoyl; and

(12) Optionally substituted mercapto.

Preferably, Q ³ to Q ⁹ include a hydrogen atom or a C _1-4 alkyl group having a substituent selected from the following groups:

(1) Optionally substituted C _6-12 aromatic hydrocarbon groups;

(2) An optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atoms;

(3) optionally substituted C _8-14 aromatic fused ring groups;

(4) An optionally substituted 5- to 14-membered aromatic condensed heterocyclic group consisting of 3 to 11 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atom;

(5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms;

(6) An optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms;

(7) optionally substituted amino groups;

(8) optionally substituted guanidino;

(9) optionally substituted hydroxyl;

(10) optionally substituted carboxy;

(11) optionally substituted carbamoyl; and,

(12) Optionally substituted mercapto.

The "optionally substituted C _6-12 aromatic hydrocarbon group", "optionally substituted 5 to 14 membered aromatic heterocyclic group, the 5 to 14 membered aromatic heterocyclic group consists of 1 to 7 carbon atoms and The composition of heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms", "optionally substituted C _8-14 aromatic condensed ring group", "optionally substituted 5 to 14 membered aromatic fused heterocyclic group, The 5- to 14-membered aromatic condensed heterocyclic group is composed of 3 to 11 carbon atoms and heteroatoms, and the heteroatoms are selected from nitrogen, oxygen and sulfur atoms", "optionally substituted carbon atoms with no more than 7 The "non-aromatic cyclic hydrocarbon group" and "optionally substituted non-aromatic heterocyclic group having no more than 7 carbon atoms" are the same as above.

(1) As the C _1-4 alkyl group having an optionally substituted C _6-12 aromatic hydrocarbon group, for example, benzyl, 4-hydroxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, Benzyl, 4-aminobenzyl, etc.

(2) As a _C1-4 alkyl group having an optionally substituted 5 to 14 membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero Atomic composition, the heteroatom is selected from nitrogen, oxygen and sulfur atoms, for example, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-imidazolylmethyl and the like are used.

(3) As the C _1-4 alkyl group having an optionally substituted C _8-14 aromatic condensed ring group, for example, 1-naphthylmethyl, 2-naphthylmethyl and the like are used.

(4) As a C _1-4 alkyl group having an optionally substituted 5 to 14 membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur atoms, for example, 3-indolylmethyl, 1-formylindol-3-ylmethyl, 2-quinolylmethyl and the like are used.

(5) As the C _1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group having a carbon number of not more than 7, for example, cyclohexylmethyl group and the like are used.

(6) As a C _1-4 alkyl group having an optionally substituted non-aromatic heterocyclic group, the number of carbon atoms of the optionally substituted non-aromatic heterocyclic group is not more than 7, using, for example, piperidine-1- base methyl etc.

(7) As the C _1-4 alkyl group having an optionally substituted amino group, for example, 2-aminoethyl group, 3-aminopropyl group, 4-aminobutyl group, 4-acetamidobutyl group and the like are used.

(8) As the C _1-4 alkyl group having an optionally substituted guanidino group, for example, 3-guanidinopropyl group, 3-(N-tosyl)guanidinopropyl group and the like are used.

(9) As the C _1-4 alkyl group having an optionally substituted hydroxyl group, for example, hydroxymethyl group, 1-hydroxyethyl group, benzyloxymethyl group and the like are used.

(10) As the C _1-4 alkyl group having an optionally substituted carboxy group, for example, carboxymethyl group, 2-carboxyethyl group, benzyloxycarbonylmethyl group and the like are used.

(11) As the C _1-4 alkyl group having an optionally substituted carbamoyl group, for example, carbamoylmethyl group, 2-carbamoylethyl group, xanthenylcarbamoyl group and the like are used.

(12) As the C _1-4 alkyl group having an optionally substituted mercapto group, for example, mercaptomethyl, 2-(methylmercapto)ethyl and the like are used.

(13) As the unsubstituted C _1-4 alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like are used.

Preferably, Q is ^a hydrogen atom, 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl, methyl, isobutyl, hydroxymethyl, carboxymethyl, 4-aminobutyl etc., more preferably 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl and the like.

Preferably Q includes carbamoylmethyl, 2-carbamoylethyl, 4-hydroxybenzyl, 4-imidazolemethyl, isobutyl, hydroxymethyl, 1 ^- hydroxyethyl, carboxymethyl, 4-aminobutyl and the like, more preferably carbamoylmethyl, 2-carbamoylethyl, 4-hydroxybenzyl and the like.

It is preferred that ^Q include benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-aminobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridyl 1-Naphthylmethyl, 1-Naphthylmethyl, 2-Naphthylmethyl, 3-Indolylmethyl, 1-Formylindol-3-ylmethyl, 2-Quinolinylmethyl, Cyclohexylmethyl, Hydroxymethyl, 1-hydroxyethyl, methyl, isopropyl, isobutyl, sec-butyl, carboxymethyl, 4-aminobutyl, etc., more preferably benzyl, 2-chlorobenzyl, 3 -chlorobenzyl, 4-chlorobenzyl, 4-aminobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolylmethyl, 2-quinolylmethyl, cyclohexylmethyl, 1-hydroxyethyl, isopropyl, isobutyl, sec-butyl, etc.

Preferably, ^Q6 is methyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, etc., more preferably carbamoylmethyl, etc.

It is preferred that Q is ⁴ -hydroxybenzyl, carbamoylmethyl, 3-pyridylmethyl, methyl, isobutyl, benzyl, 4-aminobutyl, 3-indolylmethyl, etc., More preferred are 4-hydroxybenzyl and the like.

Preferably Q is ^benzyl , 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-naphthylmethyl, 3-indolylmethyl, hydroxymethyl, cyclohexyl Methyl, sec-butyl, 1-hydroxyethyl, methyl, methyl, isobutyl, 4-aminobutyl, 3-carboxypropyl, etc., more preferably 4-pyridylmethyl, 3-ind Indolylmethyl, sec-butyl, etc.

It is preferred that ^Q is a hydrogen atom, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, carbamoyl methyl, 2-carbamoyl ethyl, ureidomethyl, acetamidomethyl, formazan Amidomethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, etc., more preferably carbamoylmethyl, ureidomethyl, etc.

Preferably, ^Q10 is 4-hydroxybenzyl, 3-indolylmethyl, methyl, 1-hydroxyethyl, 3-guanidinopropyl, etc., more preferably 3-indolylmethyl, etc.

It is preferable that Q ¹¹ is carbamoylmethyl or the like.

Preferably Q ¹² is methyl, carbamoylmethyl, etc., more preferably carbamoylmethyl, etc.

Each of ^Y1 to ^Y3 represents a group represented by the following formula:

-CON(J ¹³ )-, -CSN(J ¹³ )-, -C(J ¹⁴ )N(J ¹³ )- or -N(J ¹³ )CO-

(J ¹³ and J ¹⁴ each represent a hydrogen atom or a C _1-3 alkyl group).

As the C _1-3 alkyl represented by ^J13 and ^J14 , methyl, ethyl, propyl or isopropyl is used.

J ¹³ is a hydrogen atom.

J ¹⁴ is a hydrogen atom.

Y ¹ is preferably a group represented by the following formula: -CONH- or -CH ₂ NH- and the like.

Y ² is preferably a group represented by the following formula: -CONH- or -CH ₂ NH- and the like.

Y ³ is preferably a group represented by the following formula: -CONH- and the like.

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ , J ⁶ and Q ⁶ , J ⁷ and Q ⁷ , J ⁸ and Q ⁸ , J ⁹ and Q ⁹ , J ¹⁰ and Q ¹⁰ , J ¹¹ And Q ¹¹ and J ¹² and Q ¹² can combine together to form a ring. At this time, through C(J ³ )(Q ³ ), C(J ⁴ )(Q ⁴ ), C(J ⁵ )(Q ⁵ ), C(J ⁶ )(Q ⁶ ), C(J ⁷ )( Q ⁷ ), C(J ⁸ )(Q ⁸ ), C(J ⁹ )(Q ⁹ ), C(J ¹⁰ )(Q ¹⁰ ), C(J ¹¹ )(Q ¹¹ ) or C(J ¹² )( Q ¹² ) forms eg cyclopentane, cyclohexane, piperidine and the like.

Z ¹ and R ¹ , J ² and Q ³ , Y 1 and Q ⁴ , Y ² and Q ⁵ , ^{Y 3} and Q ⁶ , J ² and Q ⁷ , Y ² and Q ⁸ , Y ³ and Q ⁹ , J ² and Q ¹⁰ , Y ³ and Q ¹¹ and J ² and Q ¹² (preferably J ² and Q ³ , Y ¹ and Q ⁴ , Y ² and Q ⁵ , Y ³ and Q ⁶ , J ² and Q ⁷ , Y ² and Q ⁸ , Y ³ and Q ⁹ , J ² and Q ¹⁰ , Y ³ and Q ¹¹ , and J ² and Q ¹² ) can be combined to form a ring. Alternatively, the rings may be optionally substituted or annealed.

When Z ¹ and R ¹ , J ² and Q ³ , J ² and Q ⁷ , J ² and Q ¹⁰ or J ² and Q ¹² combine to form a ring, through Z ¹ -N-CH-R ¹ , J ² -C(J ³ )(Q ³ ), J ² -C(J ⁷ )(Q ⁷ ), J ² -C(J ¹⁰ )(Q ¹⁰ ) or J ² -C(J ¹² )(Q ¹² ) can Formation such as azetidine, pyrrolidine, piperidine or thiazolidine. Alternatively, the rings may be optionally substituted or annealed. Z ¹ -N-CH-R ¹ is preferably azetidine, pyrrolidine, 4-hydroxypyrrolidine, piperidine and the like.

When Y ¹ and Q ⁴ , Y ² and Q ⁵ , Y ³ and Q ⁶ , Y ² and Q ⁸ , Y ³ and Q ⁹ or Y ³ and Q ¹¹ can be combined to form a ring, through Y ¹ C(J ⁴ )(Q ⁴ ), Y ² C(J ⁵ )(Q ⁵ ), Y ³ C(J ⁶ )(Q ⁶ ), Y ² C(J ⁸ )(Q ⁸ ), Y ³ C(J ⁹ ) (Q ⁹ ) or y ³ C(J ¹¹ )(Q ¹¹ ) can form, for example, pyrrolidine-2-carbonyl, piperidine-2-carbonyl or thiazolidine-4-carbonyl. Alternatively, the rings may be optionally substituted or annealed.

General formula J ¹ -J ² -C(J ³ )(Q ³ )Y ¹ C(J ⁴ )(Q ⁴ )Y ² C(J ⁵ )(Q ⁵ )Y ³ C(J ⁶ )(Q ⁶ ) Preferable examples of the group represented by C(=Z ¹⁰ )- include:

Tyr Asn Trp Asn-,

Tyr Asn Trp D-Asn-,

Tyr Asn D-Trp Asn-,

Tyr D-Asn Trp Asn-,

D-Tyr Asn Trp Asn-,

Tyr Lys Trp Asn-,

Tyr Asp Trp Asn-,

Tyr Tyr Trp Asn-,

Tyr Leu Trp Asn-,

Tyr Asn Ala Asn-,

Tyr Asn Leu Asn-,

Tyr Asn Ser Asn-,

Tyr Asn Asp Asn-,

Tyr Asn Lys Asn-,

Ala Asn Trp Asn-,

Leu Asn Trp Asn-,

Ser Ash Trp Asn-,

Asp Asn Trp Asn-,

Lys Asn Trp Asn-,

Tyr Ash Trp(For)Asn-,

D-Tyr Asn D-Trp Asn-,

D-Tyr Asn Ala Asn-,

D-Tyr Asn Ser Asn-,

D-Tyr Asn Cha Asn-,

D-Tyr Asn Thr Asn-,

D-Tyr Asn Ile Asn-,

D-Tyr Gln Trp Asn-,

D-Tyr Thr Trp Asn-,

D-Tyr Asn Val Asn-,

D-Tyr D-Asn Trp Asn-,

D-Tyr D-Asn D-Trp Asn-,

D-Tyr Asn Phe Asn-,

D-Tyr Asn Nal(1)Asn-,

D-Tyr Asn Nal(2)Asn-,

D-Tyr Asn Phe(2Cl)Asn-,

D-Tyr Asn Phe(3Cl)Asn-,

D-Tyr Asn Phe(4Cl)Asn-,

D-Tyr Asn Phe(4NH ₂ )Asn-,

D-Tyr Asn Pya(3)Asn-,

D-Tyr D-Asn Phe Asn-,

D-Tyr D-Asn Cha Asn-,

D-Tyr D-Asn Thr Asn-,

D-Tyr Asn Pya(2)Asn-,

D-Tyr Asn Pya(4)Asn-,

D-Tyr D-Ser Trp Asn-,

D-Tyr D-His Trp Asn-,

D-Pya(3)D-Asn Cha Asn-,

D-Pya(3)D-Tyr Cha Asn-,

TyrΨ(CH ₂ NH)Asn Trp Asn-,

D-Tyr AsnΨ(CH ₂ NH)Trp Asn-,

TyrΨ(CH ₂ NH)Asn D-Trp Asn-,

D-Tyr Asn Ala(2-Qui) Asn-,

D-Tyr Asn D-Pya(4)Asn-,

D-Tyr D-Asn Pya(4)Asn-,

Tyr D-Asn Cha Asn-,

Dap D-Tyr Asn Trp Asn-

Arg D-Tyr D-Pya(4)Asn-

Arg Arg D-Tyr D-Pya(4)Asn-

Arg Acp D-Tyr D-Pya(4)Asn-

D-Arg Acp D-Tyr D-Trp Asn-

D-Arg D-Arg Acp D-Tyr D-Trp Asn-

Ac D-Arg Acp D-Tyr D-Trp Asn-

D-Dap Acp D-Tyr D-Trp Asn-

D-Nle Acp D-Tyr D-Trp Asn-

D-Arg β-Ala D-Tyr D-Trp Asn-

D-Arg γ-Abu D-Tyr D-Trp Asn-

D-Arg D-Arg γ-Abu D-Tyr D-Trp Asn-

D-Arg D-Arg D-Arg γ-Abu D-Tyr D-Trp Asn-

Gly D-Tyr D-Trp Asn-

Ac Gly D-Tyr D-Trp Asn-

D-Tyr D-Tyr D-Trp Asn-

Ac D-Tyr D-Tyr D-Trp Asn-

pGlu D-Tyr D-Trp Asn-

Tyr D-Tyr D-Trp Asn-

Ac Tyr D-Tyr D-Trp Asn-etc.

Groups represented by the general formula J ¹ -J ² -C(J ⁷ )(Q ⁷ )Y ² C(J ⁸ )(Q ⁸ )Y ³ C(J ⁹ )(Q ⁹ )C(=Z ¹⁰ )- Preferred examples of include:

Fmoc Asn Trp Asn-,

D-Asn Trp Asn-,

D-Tyr Trp Asn-,

D-Tyr D-Trp Asn-,

D-Tyr Ser Asn-,

D-Tyr Thr Asn-,

D-Tyr Ile Asn-,

D-Tyr Phe Asn-,

D-Tyr Nal(2)Asn-,

D-Pya(3)Phe Asn-,

D-Pya(3)Trp Asn-,

D-Tyr D-Pya(4)Asn-,

D-Asn Cha Asn-

D-Tyr D-Pya(4)Ala-

D-Tyr D-Pya(4)Thr-

D-Tyr Pya(4)Ala-

D-Tyr D-Trp Ala-

D-Tyr D-Trp Abu-

D-Tyr D-Phe Ala-6-aminocaproyl-

D-Tyr D-Pya(4)Asn-

Ac D-Tyr D-Pya(4)Asn-

Benzoyl D-Tyr D-Trp Asn-

Cyclopropanecarbonyl D-Tyr D-Trp Asn-

Butyryl D-Tyr D-Trp Asn-

Me D-Tyr D-Trp Asn-

Ac D-Tyr D-Trp Gln-

Ac D-Tyr D-Trp Ser-

Ac D-Tyr D-Trp Thr-

Ac D-Tyr D-Trp Alb-

Ac D-Tyr D-Trp Dap(Ac)-

Ac D-Tyr D-Trp Dap(For)-

Ac D-Tyr Trp Asn-

Ac D-NMe Tyr D-Trp Asn-

For D-Tyr D-Trp Asn-

Propionyl D-Tyr D-Trp Asn-

Amino D-Tyr D-Trp Asn-

Ac D-Ala D-Trp Asn-

Ac D-Leu D-Trp Asn-

Ac D-Phe D-Trp Asn-

Ac D-Nal(1)D-Trp Asn-

Ac D-Nal(2)D-Trp Asn-

Ac D-Lys D-Trp Asn-

Ac D-Glu D-Trp Asn-

Ac D-Tyr D-Ala Asn-

Ac D-Tyr D-Leu Asn-

Ac D-Tyr D-Phe Asn-

Ac D-Tyr D-Thr Asn-

Ac D-Tyr D-Lys Asn-

Ac D-Tyr D-Glu Asn-

Ac D-Tyr D-Trp Asp-

Ac D-Tyr D-Trp D-Asn-

Ac D-Tyr D-Trp NMeAsn-

Ac D-Tyr Pro Asn-

Ac D-Tyr D-Pya(2)Asn-

Ac D-Tyr D-Pya(3)Asn-

Ac D-Tyr D-Pro Asn-

Ac D-Tyr Tic Asn-

Ac Tyr Trp Asn-

Ac D-Tyr NMe Trp Asn-

Glycoloyl D-Tyr D-Trp Asn-

Ac D-Tyr D-Trp Gly-

Ac D-Tyr D-Trp Dap-

Ac D-Tyr D-Trp Asp(NHMe)-

Ac D-Tyr D-Trp Asp(NMe2)-etc.

Preferred examples of the group represented by the general formula J ¹ -J ² -C(J ¹⁰ )(Q ¹⁰ )Y ³ C(J ¹¹ )(Q ¹¹ )C(=Z ¹⁰ )- include:

Fmoc Trp Asn-,

Boc Tyr Asn-,

Tyr Asn-,

D-Trp Asn-,

Ac Trp Asn-,

Amino Trp Asn-,

Ac Ala Asn-,

Ac Arg Asn-,

Ac Thr Asn-

D-Tyr D-Pya(4)-

3-(4-Hydroxyphenyl)propionyl D-Trp Asn-

D-Trp Asn-

Ac D-Trp Asn-

Hexanoyl D-Trp Asn-

Cyclohexanecarbonyl D-trp Asn-

Benzoyl D-Trp Asn-

3-Pyridinepropionyl D-Trp Asn-

Adipyl D-Trp Asn-

6-aminocaproyl D-Trp Asn-

Amino D-Trp Asn-

Glycoyl D-Trp Asn- et al.

Preferred examples of the group represented by the general formula J ¹ -J ² -C(J ¹² )(Q ¹² )C(=Z ¹⁰ )- include:

Fmoc Asn-,

3-(Indol-3-yl)propionyl Asn-,

3-Indolecarbonyl Asn-,

3-IndoleacetylAsn-,

4-(Indol-3-yl)butanoyl Asn-,

Diphenylacetyl Asn-,

Hexanoyl Asn-,

Cyclohexanecarbonyl Asn-,

2-(indol-3-yl)ethylcarbamoyl (ethylcabamoyl)Asn-,

3-(3-pyridyl)propionyl Asn-,

4-Imidazole (Imidzole) acetyl Asn-,

piperidinecarbonyl Asn-,

1-piperidineacetyl Asn-,

1-Methyl-1-piperidinoacetyl (piperidinioacetyl) Asn-,

1-pyridinoacetyl (Pyridinioacetyl) Asn-,

D-glucuronide Asn-,

3-phenylpropanoyl Asn-,

3-phenylpropionyl Ala-,

Benzoyl Asn-,

Ac Asn-,

Cyclopropanecarbonyl Asn-,

2-Naphthoyl Asn- et al.

Preferred examples of the general formula J ^1- include:

A hydrogen atom,

GuAmb-,

3-(3-indolyl)propionyl-,

3-(3-pyridyl)propionyl-,

Benzoyl-,

Indole-3-carbonyl-,

indole-3-acetyl-,

Ac-,

Hexanoyl-,

Z-,

Tos-,

3-phenylpropionyl-,

2-(Indol-3-yl)ethylcarbamoyl-,

Benzyl-,

phenethyl-,

2-pyridinecarbonyl-,

4-pyridinecarbonyl-,

Propionyl-,

isobutyryl-,

cyclohexanecarbonyl-,

Phenylacetyl-,

2-Methylnicotinoyl-,

5-methylnicotinoyl-,

6-methylnicotinoyl-,

pyrazinecarbonyl-,

Cyclopropanecarbonyl-,

Trifluoroacetyl-,

(R)-3-Hydroxy-2-methylpropionyl-,

2-Hydroxyisobutyryl-,

3-furancarbonyl-,

pyrrole-2-carbonyl-,

4-imidazolecarbonyl-,

6-Hydroxynicotinoyl-,

6-chloronicotinoyl-,

6-(trifluoromethyl)nicotinoyl-,

Dimethylcarbamoyl-,

1-azetidinecarbonyl-,

2-azetidinecarbonyl-,

4-aminobenzoyl-,

4-Aminomethylbenzoyl-,

pyrrole-3-carbonyl-,

pyrimidine-4-carbonyl-,

pyrimidine-2-carbonyl-,

Pyridazine-4-carbonyl-et al.

In the transferin derivative (III) of the present invention, V' represents the following formula

(wherein, the meaning of each symbol is the same as above) The transferin derivative (I) of the group represented is the compound group disclosed in the application specification of PCT/JP03/16978, but V' represents the following formula

(wherein, the meaning of each symbol is the same as above), the group shown, or the following formula

(wherein, the meanings of the symbols are the same as above) The transferin derivatives (II) of the group represented are a new group of compounds.

Among the transferin derivatives (III), all compounds obtained by arbitrarily combining the groups of the above symbols are preferably used. Among them, the compounds shown by the following compound numbers (Tables 1 to 11) are preferable.

MS10: Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe- _NH2

1 2 3 4 5 6 7 8 9 10

Compound No. 17: [Pya(4)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Pya(4)-NH ₂

Compound No. 18: [Tyr(Me)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Tyr(Me)-NH ₂

Compound No. 19: [Phe(2F)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(2F)-NH ₂

Compound No. 23: [Tyr5]MS10

Tyr-Asn-Trp-Asn-Tyr-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 24: [Leu5]MS10

Tyr-Asn-Trp-Asn-Leu-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 30: Acetyl-MS10

Acetyl-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe- _NH2

Compound No. 31: Fmoc-MS10

Fmoc-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe- _NH2

Compound No. 38: [D-Ser5]MS10

Tyr-Asn-Trp-Asn-D-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 39: [D-Asn4]MS10

Tyr-Asn-Trp-D-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 40: [D-Trp3]MS10

Tyr-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 41: [D-Asn2]MS10

Tyr-D-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 42: [D-Tyr1]MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 44: [Lys9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Lys-Phe-NH ₂

Compound No. 45: [Ala8]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Ala-Arg-Phe-NH ₂

Compound No. 50: [Ala7]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Ala-Leu-Arg-Phe-NH ₂

Compound No. 51: [NMePhe10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-NMePhe- _NH2

Compound No. 53: des(1-3)-Fmoc-MS10

Fmoc-Asn-Ser-Phe-Gly-Leu-Arg-Phe- _NH2

Compound No. 54: des(1-2)-Fmoc-MS10

Fmoc-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 55: des(1)-Fmoc-MS10

Fmoc-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 56: [Lys2]MS10

Tyr-Lys-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 57: [Asp2]MS10

Tyr-Asp-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 58: [Tyr2]MS10

Tyr-Tyr-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 59: [Leu2]MS10

Tyr-Leu-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 60: [Pya(3)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Pya(3)-NH ₂

Compound No. 61: [Phe(4F)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(4F)-NH ₂

Compound No. 67: [Ala3]MS10

Tyr-Asn-Ala-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 68: [Leu3]MS10

Tyr-Asn-Leu-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 69: [Ser3]MS10

Tyr-Asn-Ser-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 70: [Asp3]MS10

Tyr-Asn-Asp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 71: [Lys3]MS10

Tyr-Asn-Lys-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 72: [Ala1]MS10

Ala-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 73: [Leu1]MS10

Leu-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 74: [Ser1]MS10

Ser-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 75: [Asp1]MS10

Asp-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 76: [Lys1]MS10

Lys-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 77: [Phe(4CN)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(4CN)-NH ₂

Compound No. 78: [Trp(For)3, Phe(4CN)10]MS10

Tyr-Asn-Trp(For)-Asn-Ser-Phe-Gly-Leu-Arg-Phe(4CN)-NH ₂

Compound No. 79: [Hph10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Hph-NH ₂

Compound No. 81: [NMeArg9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-NMeArg-Phe- _NH2

Compound No. 82: [Arg(Me)9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 83: [Arg(asyMe ₂ )9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(asyMe ₂ )-Phe-NH ₂

Compound No. 87: des(4-5)-Boc-MS10

Boc-Tyr-Asn-Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 88: des(4-5)-MS10

Tyr-Asn-Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 90: [Lys9, 9Ψ10, CH ₂ NH] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-LysΨ(CH ₂ NH)Phe-NH ₂

Compound No. 91: [8Ψ9, CH ₂ NH]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-LeuΨ(CH ₂ NH)Arg-Phe-NH ₂

Compound No. 97: [Har9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Har-Phe-NH ₂

Compound No. 98: [Lys(Me ₂ )9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Lys(Me ₂ )-Phe-NH ₂

Compound No. 101: [Ser7]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Ser-Leu-Arg-Phe-NH ₂

Compound No. 105: [Nle8]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Nle-Arg-Phe-NH ₂

Compound No. 107: [Val8]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Val-Arg-Phe-NH ₂

Compound No. 109: [Tyr10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Tyr-NH ₂

Compound No. 110: [Nal(2)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Nal(2)-NH ₂

Compound No. 111: [Phe(F5)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(F5)-NH ₂

Compound No. 112: [Cha10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Cha-NH ₂

Compound No. 114: des(1-3)-3-(3-indolyl)propionyl-MS10

3-(3-Indolyl)propionyl-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 121: des(1-4)-[Trp5]MS10

Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 123: [NMeLeu8]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-NMeLeu-Arg-Phe- _NH2

Compound No. 126: [NMeSer5]MS10

Tyr-Asn-Trp-Asn-NMeSer-Phe-Gly-Leu-Arg-Phe- _NH2

Compound No. 127: [D-Asn4, NMePhe6] MS10

Tyr-Asn-Trp-D-Asn-Ser-NMePhe-Gly-Leu-Arg-Phe- _NH2

Compound No. 128: [10Ψ, CSNH] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-PheΨ(CSNH)NH ₂

Compound No. 129: [Arg(symMe ₂ )9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(symMe ₂ )-Phe-NH ₂

Compound No. 130: [Phe(4Cl)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(4Cl)-NH ₂

Compound No. 131: [Phe(4NH ₂ )10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(4NH ₂ )-NH ₂

Compound No. 132: [Phe(4NO ₂ )10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(4NO ₂ )-NH ₂

Compound No. 133: [Nal(1)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Nal(1)-NH ₂

Compound No. 134: [Trp10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Trp-NH ₂

Compound No. 137: [Nle9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Nle-Phe-NH ₂

Compound No. 138: [Cit9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Cit-Phe-NH ₂

Compound No. 140: [Arg(Me)9, NMePhe10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-NMePhe-NH ₂

Compound No. 141: [D-Tyr1, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 142: [D-Tyr1, D-Trp3, Arg(Me)9] MS10

D-Tyr-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 143: [D-Trp3, Arg(Me)9] MS10

Tyr-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 144: des(1-3)-Fmoc-[Arg(Me)9]MS10

Fmoc-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 145: des(1-2)-Fmoc-[Arg(Me)9]MS10

Fmoc-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 146: [10Ψ, CSNH, D-Tyr1] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-PheΨ(CSNH)NH ₂

Compound No. 150: [Tyr6]MS10

Tyr-Asn-Trp-Asn-Ser-Tyr-Gly-Leu-Arg-Phe-NH ₂

Compound No. 151: [Nal(1)6]MS10

Tyr-Asn-Trp-Asn-Ser-Nal(1)-Gly-Leu-Arg-Phe-NH ₂

Compound No. 152: [Nal(2)6]MS10

Tyr-Asn-Trp-Asn-Ser-Nal(2)-Gly-Leu-Arg-Phe-NH ₂

Compound No. 153: [Phe(F5)6]MS10

Tyr-Asn-Trp-Asn-Ser-Phe(F5)-Gly-Leu-Arg-Phe-NH ₂

Compound No. 154: [Phe(4F)6]MS10

Tyr-Asn-Trp-Asn-Ser-Phe(4F)-Gly-Leu-Arg-Phe-NH ₂

Compound No. 156: [Cha6]MS10

Tyr-Asn-Trp-Asn-Ser-Cha-Gly-Leu-Arg-Phe-NH ₂

Compound No. 163: [6Ψ7, CH ₂ NH] MS10

Tyr-Asn-Trp-Asn-Ser-PheΨ(CH ₂ NH)Gly-Leu-Arg-Phe-NH ₂

Compound No. 165: [Dap(Gly)9]-MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Dap(Gly)-Phe-NH ₂

Compound No. 166: [6Ψ7, CSNH] MS10

Tyr-Asn-Trp-Asn-Ser-PheΨ(CSNH)Gly-Leu-Arg-Phe-NH ₂

Compound No. 169: [D-Tyr1, Ala3, Arg(Me)9] MS10

D-Tyr-Asn-Ala-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 170: [D-Tyr1, Ser3, Arg(Me)9] MS10

D-Tyr-Asn-Ser-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 171: [D-Tyr1, Cha3, Arg(Me)9] MS10

D-Tyr-Asn-Cha-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 172: [D-Tyr1, Cha6, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 173: [D-Tyr1, Ala7, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Ala-Leu-Arg(Me)-Phe-NH ₂

Compound No. 174: [D-Tyr1, Arg(Me)9, Trp10] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 176: [AzaGly7]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg-Phe-NH ₂

Compound No. 181: [D-Tyr1, Cha3, 6, Arg(Me)9] MS10

D-Tyr-Asn-Cha-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 182: [D-Tyr1, Cha3, 6, Arg(Me)9, Trp10] MS10

D-Tyr-Asn-Cha-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 183: [Phe(4NH ₂ )9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Phe(4NH ₂ )-Phe-NH ₂

Compound No. 184: [Phe(4-guanidino)9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Phe(4-guanidino)-Phe-NH ₂

Compound No. 185: [Dap(GnGly)9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Dap(GnGly)-Phe-NH ₂

Compound No. 186: [Trp(For)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Trp(For)-NH ₂

Compound No. 187: [Abu8]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Abu-Arg-Phe-NH ₂

Compound No. 189: [Ala(3-Bzt)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Ala(3-Bzt)-NH ₂

Compound No. 190: [D-Tyr1, Cha3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 191: [D-Tyr1, Ser3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Ser-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 192: [D-Tyr1, Arg(Et)9]MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Et)-Phe-NH ₂

Compound No. 193: [D-Tyr1, Arg(n-Pr)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(n-Pr)-Phe-NH ₂

Compound No. 194: [D-Tyr1, Arg(Ac)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Ac)-Phe-NH ₂

Compound No. 197: [Phe(3F)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(3F)-NH ₂

Compound No. 198: [Phe(3,4F ₂ )10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(3,4F ₂ )-NH ₂

Compound No. 199: [Phe(3,4Cl ₂ )10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(3,4Cl ₂ )-NH ₂

Compound No. 200: [Phe(3CF ₃ )10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe(3CF ₃ )-NH ₂

Compound No. 201: [Ala(2-Qui)10]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Ala(2-Qui)-NH ₂

Compound No. 203: [D-Tyr1, Cha6, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 204: [D-Tyr1, Ala7, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Ala-Leu-Arg(Me)-Phe-NH ₂

Compound No. 205: [D-Tyr1, Thr3, Arg(Me)9] MS10

D-Tyr-Asn-Thr-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 206: [D-Tyr1, Ile3, Arg(Me)9] MS10

D-Tyr-Asn-Ile-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 207: [D-Tyr1, Ser4, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Ser-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 208: [D-Tyr1, Thr4, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Thr-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 209: [D-Tyr1, Gln4, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Gln-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 210: [D-Tyr1, Ala4, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Ala-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 211: [D-Tyrl, Thr5, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Thr-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 212: [D-Tyr1, Ala5, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ala-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 213: [D-Tyr1, Val8, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Val-Arg(Me)-Phe-NH ₂

Compound No. 214: [D-Tyr1, Gln2, Arg(Me)9] MS10

D-Tyr-Gln-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 215: [D-Tyr1, Thr2, Arg(Me)9] MS10

D-Tyr-Thr-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 216: des(1)-[D-Asn2, Arg(Me)9]MS10

D-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 217: des(1)-[D-Tyr2, Arg(Me)9]MS10

D-Tyr-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 218: [N((CH ₂ ) ₃ Gn)]Gly9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-N((CH ₂ ) ₃ Gn)Gly-Phe-NH ₂

Compound No. 220: [Arg(Et)9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Et)-Phe-NH ₂

Compound No. 221: [D-Tyr1, Thr3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 222: des(1)-[D-Tyr2, AzaGly7, Arg(Me)9]MS10

D-Tyr-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 223: des(1-2)-[D-Trp3, Arg(Me)9]MS10

D-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 224: des(1)-[D-Tyr2, D-Trp3, Arg(Me)9]MS10

D-Tyr-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 225: des(1)-[D-Asn2, D-Trp3, Arg(Me)9]MS10

D-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 226: des(1)-[D-Tyr2, Ser3, Arg(Me)9]MS10

D-Tyr-Ser-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 227: des(1)-[D-Tyr2, Thr3, Arg(Me)9]MS10

D-Tyr-Thr-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 228: des(1)-[D-Tyr2, Ile3, Arg(Me)9]MS10

D-Tyr-Ile-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 229: [D-Tyr1, Val3, Arg(Me)9] MS10

D-Tyr-Asn-Val-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 230: [D-Tyr1, D-Asn2, Arg(Me)9] MS10

D-Tyr-D-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 231: [D-Tyr1, D-Asn2, D-Trp3, Arg(Me)9] MS10

D-Tyr-D-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 232: [D-Tyr1, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-S er-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 233: [D-Tyr1, Ile3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Ile-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 234: [D-Tyr1, Val3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Val-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 235: [D-Tyr1, Ala3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Ala-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 236: [D-Tyr1, D-Trp3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 237: [D-Tyr1, D-Asn2, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 238: [D-Tyr1, D-Asn2, D-Trp3, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 239: des(1)-[D-Tyr2, Ser3, AzaGly7, Arg(Me)9]MS10

D-Tyr-Ser-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 240: des(1)-[D-Tyr2, Ile3, AzaGly7, Arg(Me)9]MS10

D-Tyr-Ile-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 241: des(1)-[D-Tyr2, Thr3, AzaGly7, Arg(Me)9]MS10

D-Tyr-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 242: des(1)-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9]MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 244: [D-Tyr1, Phe3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Phe-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 245: [D-Tyr1, Nal(1)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Nal(1)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 246: [D-Tyr1, Nal(2)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Nal(2)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 247: [D-Tyrl, Phe(2Cl)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Phe(2Cl)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 248: [D-Tyr1, Phe(3Cl)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Phe(3Cl)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 249: [D-Tyr1, Phe(4Cl)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Phe(4Cl)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 250: [D-Tyr1, Phe(4NH2)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Phe(4NH ₂ )-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 251: [D-Tyr1, Pya(3)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Pya(3)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 252: [D-Tyr1, D-Ala3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-D-Ala-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 253: [D-Tyr1, Pro3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Pro-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 254: des(1)-[D-Tyr2, Phe3, AzaGly7, Arg(Me)9]MS10

D-Tyr-Phe-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 255: des(1)-[D-Tyr2, Nal(2)3, AzaGly7, Arg(Me)9]MS10

D-Tyr-Nal(2)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 256: des(1)-[D-Pya(3)2, Phe3, AzaGly7, Arg(Me)9]MS10

D-Pya(3)-Phe-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 257: [D-Tyr1, D-Asn2, Phe3, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Asn-Phe-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 258: [D-Pya(3)1, AzaGly7, Arg(Me)9] MS10

D-Pya(3)-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 259: [D-Ala1, AzaGly7, Arg(Me)9] MS10

D-Ala-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 260: des(1-3)-3-(3-indolyl)propionyl-[AzaGly7, Arg(Me)9]MS10

3-(3-Indolyl)propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 261: [7Ψ8, CH ₂ NH]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-GlyΨ(CH ₂ NH)Leu-Arg-Phe-NH ₂

Compound No. 265: des(1-3)-indole-3-carbonyl-[AzaGly7, Arg(Me)9]MS10

Indole-3-carbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 266: des(1-3)-indole-3-acetyl-[AzaGly7, Arg(Me)9]MS10

Indole-3-acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 267: des(1-3)-4-(3-indolyl)butanoyl-[AzaGly7, Arg(Me)9]MS10

4-(3-Indolyl)butyryl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 268: des(1-3)-diphenylacetyl-[AzaGly7, Arg(Me)9]MS10

Diphenylacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 269: des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9]MS10

3-Phenylpropanoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 270: [D-Tyr1, Phe3, Ser-Phe5, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Phe-Asn-Ser-Phe-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 271: des(1-2)-[AzaGly7, Arg(Me)9]MS10

Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 272: des(1-2)-acetyl-[AzaGly7, Arg(Me)9]MS10

Acetyl-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 273: des(1-2)-amidino-[AzaGly7, Arg(Me)9]MS10

Amidino-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 274: des(1-2)-acetyl-[Ala3, AzaGly7, Arg(Me)9]MS10

Acetyl-Ala-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 275: des(1-2)-acetyl-[Arg3, AzaGly7, Arg(Me)9]MS10

Acetyl-Arg-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 276: des(1-2)-acetyl-[Thr3, AzaGly7, Arg(Me)9]MS10

Acetyl-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 277: des(1-3)-n-hexanoyl-[AzaGly7, Arg(Me)9]MS10

n-Hexanoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 278: des(1-3)-cyclohexanecarbonyl-[AzaGly7, Arg(Me)9]MS10

Cyclohexanecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 279: des(1-3)-2-(indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9]MS10

2-(Indol-3-yl)ethylcarbamoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 281: [D-Tyr1, Pya(2)6, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Pya(2)-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 282: [D-Tyr1, Pya(4)6, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Pya(4)-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 283: [D-Tyr1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 284: [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Asn-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 285: [D-Tyr1, Pya(2)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Pya(2)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 286: [D-Tyr1, Pya(4)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 287: [D-Tyr1, D-Ser2, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Ser-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 288: [D-Tyr1, D-His2, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-His-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 289: des(1)-[D-Pya(3)2, AzaGly7, Arg(Me)9]MS10

D-Pya(3)-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 290: [D-Pya(3)1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10

D-Pya(3)-D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 291: [D-Pya(3)1, D-Tyr2, Cha3, AzaGly7, Arg(Me)9] MS10

D-Pya(3)-D-Tyr-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 293: [4Ψ5, CH ₂ NH]MS10

Tyr-Asn-Trp-AsnΨ(CH ₂ NH)Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 294: [1Ψ2, CH ₂ NH]MS10

TyrΨ(CH ₂ NH)Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 295: [2Ψ3, CH ₂ NH]MS10

Tyr-AsnΨ(CH ₂ NH)Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 296: [6Ψ7, CSNH, D-Tyr1, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-PheΨ(CSNH)Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 297: [D-Tyr1, Thr5, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 298: [D-Tyr1, D-Asn2, Thr5, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Asn-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 299: [1Ψ2, CH ₂ NH, AzaGly7, Arg(Me)9]-MS10

TyrΨ(CH ₂ NH)Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 300: [1Ψ2, CH ₂ NH, D-Trp3, AzaGly7, Arg(Me)9]-MS10

TyrΨ(CH ₂ NH)Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 301: [D-Tyr1, Ala(2-Qui)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-Ala(2-Qui)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 302: [D-Tyr1, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-Asn-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 303: [D-Tyr1, D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9] MS10

D-Tyr-D-Asn-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 304: [D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9] MS10

Tyr-D-Asn-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 305: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 306: [D-Pya(4)1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10

D-Pya(4)-D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 307: [7Ψ8, CH ₂ NH, D-Tyr1, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-GlyΨ(CH ₂ NH)Leu-Arg(Me)-Phe-NH ₂

Compound No. 308: [6Ψ7, CH ₂ NH, D-Tyr1, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-PheΨ(CH ₂ NH)Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 310: [Nar9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Nar-Phe-NH ₂

Compound No. 311: [Nar(Me)9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Nar(Me)-Phe-NH ₂

Compound No. 312: [Har(Me)9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Har(Me)-Phe-NH ₂

Compound No. 313: [Dab9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Dab-Phe-NH ₂

Compound No. 314: [Orn9]MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Orn-Phe-NH ₂

Compound No. 315: des(1)-[D-Asn2, Cha3, AzaGly7, Arg(Me)9]MS10

D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 316: [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg(Me)9, Phe(4F)10] MS10

D-Tyr-D-Asn-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂

Compound No. 317: [D-Tyr1, D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9, Phe(4F)10] MS10

D-Tyr-D-Asn-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂

Compound No. 318: [D-Tyr1, AzaGly7, Arg(Me)9, Phe(4F)10] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂

Compound No. 319: [6Ψ7, NHCO, D-Tyr1, Arg(Me)9] MS10

D-Tyr-Asn-Trp-Asn-Ser-PheΨ(NHCO)Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 322: des(1-3)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9]MS10

3-(3-pyridyl)propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 323: des(1-3)-4-imidazoleacetyl-[AzaGly7, Arg(Me)9]MS10

4-Imidazoleacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 324: des(1-3)-4-piperidinecarbonyl-[AzaGly7, Arg(Me)9]MS10

Piperidinecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 325: des(1-3)-1-piperidineacetyl-[AzaGly7, Arg(Me)9]MS10

1-Piperidineacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 326: des(1-3)-1-Methylpiperidinio-1-acetyl-[AzaGly7, Arg(Me)9]MS10

1-Methylpiperidino-1-acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 327: des(1-3)-1-pyridylacetyl-[AzaGly7, Arg(Me)9]MS10

1-Pyridinioacetyl (Pyridinioacetyl)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 328: des(1-3)-D-glucuronide-[AzaGly7, Arg(Me)9]MS10

D-Glucuronide-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 375: 2-Aminoethyl-Gly-[D-Tyr1, Arg(Me)9]MS10

2-Aminoethyl-Gly-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 385: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 386: des(1-3)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

3-(3-Pyridyl)propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 387: Dap-[D-Tyr1, Arg(Me)9]MS10

Dap-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 397: Methylthiocarbamoyl-Sar-[D-Tyr1, Arg(Me)9]MS10

Methylthiocarbamoyl-Sar-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 400: (S)-1-(quinolin-8-yl-carbamoyl)-4-pentylthiocarbamoyl-[D-Tyr1, Arg(Me)9]MS10

(S)-1-(quinolin-8-yl-carbamoyl)-4-pentylthiocarbamoyl-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg(Me) -Phe-NH ₂

Compound No. 481: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har-Trp-NH ₂

Compound No. 486: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Orn9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Orn-Phe-NH ₂

Compound No. 487: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Lys9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Lys-Phe-NH ₂

Compound No. 488: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har-Phe-NH ₂

Compound No. 489: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har(Me)9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har(Me)-Phe-NH ₂

Compound No. 490: des(1)-[D-Tyr2, Pya(4)3, AzaGly7, Arg(Me)9]MS10

D-Tyr-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 491: des(1)-[D-Tyr2, D-Pya(4)3, Trp5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Trp-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 492: des(1)-[D-Tyr2, D-Pya(4)3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 493: des(1)-[D-Tyr2, D-Pya(4)3, Thr4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Thr-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 494: des(1,4)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 495: des(1-3)-[D-Tyr4, Pya(4)5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-Pya(4)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 496: des(1)-[D-Tyr2, D-Pya(4)3, Cha6, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 497: des(1)-[D-Tyr2, D-Pya(4)3, Cha6, Ala7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Cha-Ala-Leu-Arg(Me)-Trp-NH ₂

Compound No. 498: des(1)-[D-Tyr2, D-Pya(4)3, Ile5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ile-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 499: des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 500: des(1-3)-3-phenylpropionyl-[Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 501: des(1)-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 502: des(1)-[D-Tyr2, Pya(4)3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-Pya(4)-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 503: des(1)-[D-Tyr2, D-Trp3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 504: [Acp1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10

Acp-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 505: des(1-3)-3-phenylpropionyl-[Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 506: des(1-3)-3-phenylpropionyl-[Ile5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ile-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 507: des(1-3)-3-phenylpropionyl-[Trp6, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Trp-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 508: des(1-3)-3-phenylpropionyl-[Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 509: des(1-3)-benzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 510: des(1-3)-Ac-[AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 511: des(1)-[D-Tyr2, D-Trp3, Ala4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Ala-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 512: des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 513: des(1)-[D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 514: des(1)-[D-Tyr2, D-Phe3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Phe-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 515: des(1)-[D-Tyr2, D-Pya(4)3, Val5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 516: des(1)-Ac-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 517: des(1-3)-3-phenylpropionyl-[Hyp5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Asn-Hyp-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 518: des(1-3)-3-phenylpropionyl-[Cha6, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 519: des(1-3)-phenylacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Phenylacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 521: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg-Phe-NH ₂

Compound No. 522: des(1-3)-benzoyl-[Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 523: des(1-3)-benzoyl-[Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 524: des(1-3)-3-phenylpropionyl-[Pro5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Asn-Pro-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 527: des(1)-[D-Tyr2, D-Pya(4)3, Hyp5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Hyp-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 528: des(1)-[D-Tyr2, D-Pya(4)3, Pro5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Pro-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 529: des(1)-[D-Tyr2, D-Pya(4)3, Tle5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Tle-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 530: des(1)-[D-Tyr2, D-Pya(4)3, Phg5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Phg-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 531: des(1-3)-3-phenylpropionyl-[Pic(2)5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Pic(2)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 532: des(1-3)-3-phenylpropionyl-[Aze(2)5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Aze(2)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 533: des(1-3)-3-phenylpropionyl-[D-Pro5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-D-Pro-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 534: des(1-3)-cyclopropanecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Cyclopropanecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 535: des(1-3)-2-naphthoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

2-Naphthoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 536: [Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10

Arg-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 537: Arg-[Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

Arg-Arg-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 538: Arg-[Acp1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

Arg-Acp-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 539: des(1)-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 540: des(1)-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 541: D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 542: D-Arg-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Arg-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 545: des(1-3)-benzoyl-[Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Ser-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 546: des(1-3)-3-phenylpropionyl-[Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser(Ac)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 547: des(1)-[D-Tyr2, D-Pya(4)3, Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser(Ac)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 548: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, 10Ψ, CSNH]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-PheΨ(CSNH)NH ₂

Compound No. 550: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 551: Ac-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 552: D-Dap-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 553: D-Nle-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Nle-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 554: D-Arg-[β-Ala1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-β-Ala-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 555: D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 556: D-Arg-D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 557: D-Arg-D-Arg-D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-D-Arg-D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 558: des(1)-Ac-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 559: des(1-2)-3-(4-hydroxyphenyl)propionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

3-(4-Hydroxyphenyl)propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 561: D-Arg-[Acp1, D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-Acp-D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 562: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 563: des(1)-Ac-[D-Tyr2, D-Trp3, Aze(2)5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Aze(2)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 564: des(1)-Ac-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 565: des(1)-benzoyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 566: des(1)-cyclopropanecarbonyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9,

Trp10] MS10

Cyclopropanecarbonyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 567: des(1)-butyryl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Butyryl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 568: Ac-[D-Arg1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Arg-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 569: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, 6Ψ7, CH ₂ NH, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-PheΨ(CH ₂ NH)Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 570: des(1)-Me-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Me-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 571: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 572: des(1)-[D-Trp2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Trp-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 573: des(1)-Ac-[D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 576: des(1)-Ac-[D-Tyr2, D-Trp3, Gln4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Gln-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 577: des(1)-Ac-[D-Tyr2, D-Trp3, Ser4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Ser-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 578: des(1)-Ac-[D-Tyr2, D-Trp3, Thr4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Thr-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 579: des(1)-Ac-[D-Tyr2, D-Trp3, Alb4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 580: des(1)-Ac-[D-Tyr2, D-Trp3, Ser(Me)5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Ser(Me)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 584: des(1)-Ac-[D-Tyr2, D-Trp3, Dap(Ac)4, AzaGly7, Arg(Me)9, trp10]MS10

Ac-D-Tyr-D-Trp-Dap(Ac)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 585: des(1)-Ac-[D-Tyr2, D-Trp3, Dap(For)4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Dap(For)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 586: des(1)-Ac-[D-Tyr2, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Trp-Asn-Thr-D-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 589: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Nal(2)10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂

Compound No. 590: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Thi10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Thi-NH ₂

Compound No. 591: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Tyr10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Tyr-NH ₂

Compound No. 592: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Phe(4F)10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂

Compound No. 594: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Hph10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Hph-NH ₂

Compound No. 595: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Cha10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Cha-NH ₂

Compound No. 596: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Leu10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Leu-NH ₂

Compound No. 597: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 598: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 599: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Orn9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Orn-Trp-NH ₂

Compound No. 600: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂

Compound No. 601: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 602: des(1)-Ac-[D-NMe Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-NMeTyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 603: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Thr-D-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 604: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Tos)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Tos)-Trp-NH ₂

Compound No. 605: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(NO2)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(NO2)-Trp-NH ₂

Compound No. 607: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me2)asym9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me2)asym-Trp-NH ₂

Compound No. 608: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me2)sym9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me2)sym-Trp-NH ₂

Compound No. 609: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Et)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Et)-Trp-NH ₂

Compound No. 610: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys(Me2)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Lys(Me2)-Trp-NH ₂

Compound No. 611: des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 612: des(1)-For-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 613: des(1)-propionyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 614: des(1)-amidino-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Amidino-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 615: des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 616: des(1)-Ac-[D-Ala2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Ala-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 617: des(1)-Ac-[D-Leu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Leu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 618: des(1)-Ac-[D-Phe2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 619: des(1)-Ac-[D-Nal(1)2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Nal(1)-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 620: des(1)-Ac-[D-Nal(2)2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Nal(2)-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 621: des(1)-Ac-[D-Lys2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Lys-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 622: des(1)-Ac-[D-Glu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Glu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 623: des(1)-Ac-[D-Tyr2, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 624: des(1)-Ac-[D-Tyr2, Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 625: des(1)-Ac-[D-Tyr2, D-Ala3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 626: des(1)-Ac-[D-Tyr2, D-Leu3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 627: des(1)-Ac-[D-Tyr2, D-Phe3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 628: des(1)-Ac-[D-Tyr2, D-Thr3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Thr-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 629: des(1)-Ac-[D-Tyr2, D-Lys3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 630: des(1)-Ac-[D-Tyr2, D-Glu3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 631: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Ala6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Ala-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 632: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Leu6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Leu-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 633: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Lys6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Lys-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 634: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Glu6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Glu-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 635: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Pya(4)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Pya(4)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 636: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, MePhe6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-MePhe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 637: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 638: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 639: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Lys-Trp-NH ₂

Compound No. 641: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ala8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ala-Arg(Me)-Trp-NH ₂

Compound No. 642: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Val8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Val-Arg(Me)-Trp-NH ₂

Compound No. 643: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Phe8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Phe-Arg(Me)-Trp-NH ₂

Compound No. 644: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ser8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ser-Arg(Me)-Trp-NH ₂

Compound No. 645: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Har9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Har-Trp-NH ₂

Compound No. 646: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Har(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Har(Me)-Trp-NH ₂

Compound No. 647: des(1)-Ac-[D-Tyr2, D-Trp3, Asp4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asp-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 648: [Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 649: Ac-[Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 650: [D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 651: Ac-[D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

Ac-D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 652: des(1)-pGlu-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

pGlu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 653: des(1)-Ac-[D-Tyr2, D-Trp3, D-Asn4, Thr5, AzaGly7, Arg(Me)9, Typ10]MS10

Ac-D-Tyr-D-Trp-D-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 654: des(1)-Ac-[D-Tyr2, D-Trp3, D-Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-D-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 655: des(1)-Ac-[D-Tyr2, D-Trp3, MeAsn4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-MeAsn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 656: des(1)-Ac-[D-Tyr2, D-Trp3, MeSer5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-MeSer-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 657: des(1)-Ac-[D-Tyr2, Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 658: des(1)-Ac-[D-Tyr2, D-Pya(2)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(2)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 659: des(1)-Ac-[D-Tyr2, D-Trp3, allo-Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-allo-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 660: des(1)-Ac-[D-Tyr2, D-Pya(3)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(3)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 661: des(1)-Ac-[D-Tyr2, D-Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 662: des(1)-Ac-[D-Tyr2, Tic3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Tic-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 663: des(1)-Ac-[D-Trp2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 664: des(1)-Ac-[Tyr2, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 665: des(1-2)-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 666: des(1-2)-Ac-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 667: des(1-2)-hexanoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Hexanoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 668: des(1-2)-cyclohexanecarbonyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Cyclohexanecarbonyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 669: des(1-2)-benzoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 670: des(1-2)-3-pyridinepropionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Pyridinepropionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 671: des(1-2)-adipyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Adipionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 672: des(1)-Ac-[D-Tyr2, NMeTrp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-NMeTrp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 674: des(1-2)-6-aminocaproyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

6-aminocaproyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 675: [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 676: Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 677: Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Nva8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Nva-Arg(Me)-Trp-NH ₂

Compound No. 678: Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ile8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ile-Arg(Me)-Trp-NH ₂

Compound No. 679: des(1-2)-amidino-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Amidino-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 680: des(1-2)-glycolyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Glycoloyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 681: des(1)-glycoloyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Glycoloyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 682: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Gln8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Gln-Arg(Me)-Trp-NH ₂

Compound No. 685: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 686: des(1)-Ac-[D-Tyr2, D-Trp3, Gly4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Gly-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 688: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Pya(4)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Pya(4)-Trp-NH ₂

Compound No. 689: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, D-Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-D-Trp-NH ₂

Compound No. 691: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Tyr-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 692: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Trp6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Trp-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 693: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr(Me)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Tyr(Me)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 694: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Nal(2)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Nal(2)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 695: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Thi6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Thi-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 696: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Cha6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Cha-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 698: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Abu8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Abu-Arg(Me)-Trp-NH ₂

Compound No. 699: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, γMeLeu8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-γMeLeu-Arg(Me)-Trp-NH ₂

Compound No. 700: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Aib8,, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Aib-Arg(Me)-Trp-NH ₂

Compound No. 701: des(1)-Ac-[D-Tyr2, D-Trp3, Dap4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Dap-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 702: des(1)-Ac-[D-Tyr2, D-Trp3, Asp(NHMe)4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asp(NHMe)-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 703: des(1)-Ac-[D-Tyr2, D-Trp3, Asp(NMe2)4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asp(NMe2)-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

However, the transferin derivative (III) of the present invention does not include a peptide formed by the following amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1 (natural human transferin or its peptide fragment (partialpeptide)), said The amino acid sequence is 1-54 (compound number 1), 2-54, 3-54, 4-54, 5-54, 6-54, 7-54, 8-54, 9-54, 10-54, 11- 54, 12-54, 13-54, 14-54, 15-54, 16-54, 17-54, 18-54, 19-54, 20-54, 21-54, 22-54, 23-54, 24-54, 25-54, 26-54, 27-54, 28-54, 29-54, 30-54, 31-54, 32-54, 33-54, 34-54, 35-54, 36- 54, 37-54, 38-54, 39-54, 40-54 (Compound No. 2), 41-54, 42-54 (Compound No. 32), 43-54, 44-54, 45-54 (Compound No. 3), the amino acid sequence of 46-54 (Compound No. 4), 47-54, 48-54 or 49-54.

Among the transferin derivatives (II), all compounds obtained by arbitrarily combining the groups indicated by the symbols are preferably used. Among them, the compounds indicated by the following compound numbers are preferable.

Compound No. 332: des(1-5)-GuAmb-[AzaGly7, Arg(Me)9]MS10

GuAmb-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 333: des(1-5)-GuAmb-[Arg(Me)9]MS10

GuAmb-Phe-Gly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 334: des(1-5)-GuAmb-[AzaGly7, Arg(Me)9, Trp10]MS10

GuAmb-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 339: des(1-5)-3-(3-indolyl)propionyl-[AzaGly7, Arg(Me)9]MS10

3-(3-Indolyl)propionyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 340: des(1-5)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9]MS10

3-(3-pyridyl)propionyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 341: des(1-5)-benzoyl-[AzaGly7, Arg(Me)9]MS10

Benzoyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 344: des(1-5)-indole-3-carbonyl-[AzaGly7, Arg(Me)9]MS10

Indole-3-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 345: des(1-5)-indole-3-acetyl-[AzaGly7, Arg(Me)9]MS10

Indole-3-acetyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 346: des(1-5)-Ac-[AzaGly7, Arg(Me)9]MS10

Ac-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 347: des(1-5)-n-hexanoyl-[AzaGly7, Arg(Me)9]MS10

n-Hexanoyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 348: des(1-5)-Z-[AzaGly7, Arg(Me)9]MS10

Z-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 349: des(1-5)-Tos-[AzaGly7, Arg(Me)9]MS10

Tos-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 351: des(1-5)-benzoyl-MS10

Benzoyl-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 352: des(1-5)-3-(3-indolyl)propionyl-MS10

3-(3-Indolyl)propionyl-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 353: des(1-5)-benzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 354: des(1-5)-3-(3-indolyl)propionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

3-(3-Indolyl)propionyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 358: des(1-5)-Ac-[AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 362: des(1-6)-3-phenylpropionyl-[AzaGly7, Arg(Me)9]MS10

3-Phenylpropionyl-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 364: des(1-5)-2-(indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9]MS10

2-(Indol-3-yl)ethylcarbamoyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 366: des(1-5)-n-hexanoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

n-Hexanoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 367: des(1-5)-Z-[AzaGly7, Arg(Me)9, Trp10]MS10

Z-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 368: des(1-5)-Tos-[AzaGly7, Arg(Me)9, Trp10]MS10

Tos-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 369: des(1-5)-2-(indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

2-(Indol-3-yl)ethylcarbamoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 373: des(1-6)-(2S)-2-acetoxy-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

(2S)-2-Acetoxy-3-phenylpropionyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 374: des(1-6)-Z-[AzaGly7, Arg(Me)9, Trp10]MS10

Z-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 378: des(1-6)-diphenylacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Diphenylacetyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 379: des(1-6)-(2S)-2-(3-indolylpropionyloxy)-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

(2S)-2-(3-Indolylpropionyloxy)-3-phenylpropionyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 380: des(1-6)-(2S)-2-benzoyl-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

(2S)-2-Benzoyl-3-phenylpropionyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 392: des(1-5)-benzoyl-[Ala6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Ala-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 393: des(1-6)-dibenzylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Dibenzylcarbamoyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 408: des(1-6)-1-oxo-isochroman-3-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

1-Oxo-isochroman-3-carbonyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 412: des(1-6)-(2R)-2-benzoyl-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

(2R)-2-Benzoyl-3-phenylpropionyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 417: des(1-6)-benzylphenethylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Benzylphenethylcarbamoyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 421: des(1-5)-benzoyl-[6Ψ7, CH2O, Arg(Me)9, Trp10]MS10

Benzoyl-PheΨ(CH2O)Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 423: des(1-5)-benzoyl-[6Ψ7, NHCO, Arg(Me)9, Trp10]MS10

Benzoyl-PheΨ(NHCO)Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 428: des(1-6)-dibenzylaminocarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Dibenzylaminocarbamoyl-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 431: des(1-5)-benzoyl-[Azaphe6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-AzaPhe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 432: des(1-5)-3-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

3-Pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 434: des(1-7)-dibenzylaminocarbamoylacetyl-[Arg(Me)9, Trp10]MS10

Dibenzylaminocarbamoylacetyl-Leu-Arg(Me)-Trp-NH ₂

Compound No. 435: des(1-5)-2-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

2-Pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 436: des(1-5)-4-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

4-Pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 437: des(1-5)-propionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Propionyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 438: des(1-5)-isobutyryl-[AzaGly7, Arg(Me)9, Trp10]MS10

Isobutyryl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 439: des(1-5)-cyclohexanecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Cyclohexanecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 440: des(1-5)-phenylacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Phenylacetyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 441: des(1-5)-benzoyl-[Pya(2)6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Pya(2)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 442: des(1-5)-benzoyl-[Pya(4)6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Pya(4)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 443: des(1-5)-2-methylnicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

2-Methylnicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 444: des(1-5)-5-methylnicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

5-Methylnicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 445: des(1-5)-6-methylnicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

6-Methylnicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 446: des(1-5)-pyrazinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Pyrazinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 447: des(1-5)-cyclopropanecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Cyclopropanecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 448: des(1-5)-trifluoroacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Trifluoroacetyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 449: des(1-5)-benzoyl-[Cha6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Cha-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 450: des(1-5)-benzyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Benzyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 451: des(1-5)-cyclopropanecarbonyl-[Cha6, AzaGly7, Arg(Me)9, Trp10]MS10

Cyclopropanecarbonyl-Cha-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 452: des(1-5)-(R)-3-hydroxy-2-methylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

(R)-3-Hydroxy-2-methylpropionyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 453: des(1-5)-2-hydroxyisobutyryl-[AzaGly7, Arg(Me)9, Trp10]MS10

2-Hydroxyisobutyryl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 454: des(1-5)-3-furancarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

3-Furancarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 455: des(1-5)-pyrrole-2-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Pyrrole-2-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 459: des(1-5)-4-imidazolecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

4-Imidazolecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 460: des(1-5)-4-pyridinecarbonyl-[AzaGly7, Val8, Arg(Me)9, Trp10]MS10

4-Pyridinecarbonyl-Phe-AzaGly-Val-Arg(Me)-Trp-NH ₂

Compound No. 461: des(1-5)-4-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Nal(2)10]MS10

4-Pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂

Compound No. 462: des(1-5)-6-hydroxynicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

6-Hydroxynicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 463: des(1-5)-6-chloronicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

6-Chloronicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 464: des(1-5)-6-(trifluoromethyl)nicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

6-(Trifluoromethyl)nicotinoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 466: des(1-5)-2-azetidinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

2-Azetidinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 467: des(1-5)-dimethylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Dimethylcarbamoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 468: des(1-5)-1-azetidinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

1-Azetidinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 471: des(1-5)-4-pyridinecarbonyl-[AzaGly7, Arg(Me)9]MS10

4-Pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 472: des(1-5)-4-aminobenzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

4-Aminobenzoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 473: des(1-5)-4-aminomethylbenzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

4-Aminomethylbenzoyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 474: des(1-5)-pyrrole-3-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Pyrrole-3-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 475: des(1-5)-pyrimidine-4-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Pyrimidine-4-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 477: des(1-5)-4-pyridinecarbonyl-[AzaGly7, Orn9, Trp10]MS10

4-Pyridinecarbonyl-Phe-AzaGly-Leu-Orn-Trp-NH ₂

Compound No. 478: des(1-5)-4-pyridinecarbonyl-[AzaGly7, Har9, Trp10]MS10

4-Pyridinecarbonyl-Phe-AzaGly-Leu-Har-Trp-NH ₂

Compound No. 479: des(1-5)-pyrimidine-2-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Pyrimidine-2-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 480: des(1-5)-pyridazine-4-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Pyridazine-4-carbonyl-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 481: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har-Trp-NH ₂

Compound No. 486: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Orn9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Orn-Phe-NH ₂

Compound No. 487: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Lys9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Lys-Phe-NH ₂

Compound No. 488: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har-Phe-NH ₂

Compound No. 489: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har(Me)9]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Har(Me)-Phe-NH ₂

Compound No. 490: des(1)-[D-Tyr2, Pya(4)3, AzaGly7, Arg(Me)9]MS10

D-Tyr-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 491: des(1)-[D-Tyr2, D-Pya(4)3, Trp5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Trp-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 492: des(1)-[D-Tyr2, D-Pya(4)3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 493: des(1)-[D-Tyr2, D-Pya(4)3, Thr4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Thr-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 494: des(1,4)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 495: des(1-3)-[D-Tyr4, Pya(4)5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-Pya(4)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 496: des(1)-[D-Tyr2, D-Pya(4)3, Cha6, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 497: des(1)-[D-Tyr2, D-Pya(4)3, Cha6, Ala7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Cha-Ala-Leu-Arg(Me)-Trp-NH ₂

Compound No. 498: des(1)-[D-Tyr2, D-Pya(4)3, Ile5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ile-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 499: des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 500: des(1-3)-3-phenylpropionyl-[Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 501: des(1)-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 502: des(1)-[D-Tyr2, Pya(4)3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-Pya(4)-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 503: des(1)-[D-Tyr2, D-Trp3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 504: [Acp1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10

Acp-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 505: des(1-3)-3-phenylpropionyl-[Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 506: des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ile-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 507: des(1-3)-3-phenylpropionyl-[Trp6, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Trp-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 508: des(1-3)-3-phenylpropionyl-[Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 509: des(1-3)-benzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 510: des(1-3)-Ac-[AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 511: des(1)-[D-Tyr2, D-Trp3, Ala4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Ala-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 512: des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 513: des(1)-[D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 514: des(1)-[D-Tyr2, D-Phe3, Ala4, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Phe-Ala-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 515: des(1)-[D-Tyr2, D-Pya(4)3, Val5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 516: des(1)-Ac-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 517: des(1-3)-3-phenylpropionyl-[Hyp5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Asn-Hyp-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 518: des(1-3)-3-phenylpropionyl-[Cha6, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser-Cha-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 519: des(1-3)-phenylacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Phenylacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 521: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg-Phe-NH ₂

Compound No. 522: des(1-3)-benzoyl-[Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 523: des(1-3)-benzoyl-[Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 524: des(1-3)-3-benzopropionyl-[Pro5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropionyl-Asn-Pro-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 527: des(1)-[D-Tyr2, D-Pya(4)3, Hyp5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Hyp-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 528: des(1)-[D-Tyr2, D-Pya(4)3, Pro5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Pro-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 529: des(1)-[D-Tyr2, D-Pya(4)3, Tle5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Tle-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 530: des(1)-[D-Tyr2, D-Pya(4)3, Phg5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Phg-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 531: des(1-3)-3-phenylpropionyl-[Pic(2)5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Pic(2)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 532: des(1-3)-3-phenylpropionyl-[Aze(2)5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Aze(2)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 533: des(1-3)-3-phenylpropionyl-[D-Pro5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-D-Pro-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 534: des(1-3)-cyclopropanecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10

Cyclopropanecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 535: des(1-3)-2-naphthoyl-[AzaGly7, Arg(Me)9, Trp10]MS10

2-Naphthoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 536: [Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10

Arg-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 537: Arg-[Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

Arg-Arg-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 538: Arg-[Acp1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

Arg-Acp-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 539: des(1)-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 540: des(1)-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 541: D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 542: D-Arg-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Arg-D-Arg-Acp-D-Tyr-D-Typ-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 545: des(1-3)-benzoyl-[Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-Asn-Ser-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 546: des(1-3)-3-phenylpropionyl-[Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Phenylpropanoyl-Asn-Ser(Ac)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 547: des(1)-[D-Tyr2, D-Pya(4)3, Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Ser(Ac)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 548: des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, 10Ψ, CSNH]MS10

D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-PheΨ(CSNH)NH ₂

Compound No. 550: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 551: Ac-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Typ10]MS10

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 552: D-Dap-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 553: D-Nle-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Nle-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 554: D-Arg-[β-Ala1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-β-Ala-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 555: D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 556: D-Arg-D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 557: D-Arg-D-Arg-D-Arg-[γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-D-Arg-D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 558: des(1)-Ac-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 559: des(1-2)-3-(4-hydroxyphenyl)propionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

3-(4-Hydroxyphenyl)propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 561: D-Arg-[Acp1, D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10] MS10

D-Arg-Acp-D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 562: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 563: des(1)-Ac-[D-Tyr2, D-Trp3, Aze(2)5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Aze(2)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 564: des(1)-Ac-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 565: des(1)-benzoyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 566: des(1)-cyclopropanecarbonyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Cyclopropanecarbonyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 567: des(1)-butyryl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Butyryl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 568: Ac-[D-Arg1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Arg-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 569: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, 6Ψ7, CH ₂ NH, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-PheΨ(CH ₂ NH)Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 570: des(1)-Me-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Me-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 571: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 572: des(1)-[D-Trp2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10

D-Trp-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 573: des(1)-Ac-[D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 576: des(1)-Ac-[D-Tyr2, D-Trp3, Gln4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Gln-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 577: des(1)-Ac-[D-Tyr2, D-Trp3, Ser4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Ser-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 578: des(1)-Ac-[D-Tyr2, D-Trp3, Thr4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Thr-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 579: des(1)-Ac-[D-Tyr2, D-Trp3, Alb4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 580: des(1)-Ac-[D-Tyr2, D-Trp3, Ser(Me)5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Ser(Me)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 584: des(1)-Ac-[D-Tyr2, D-Trp3, Dap(Ac)4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Dap(Ac)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 585: des(1)-Ac-[D-Tyr2, D-Trp3, Dap(For)4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Dap(For)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 586: des(1)-Ac-[D-Tyr2, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Trp-Asn-Thr-D-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 589: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Nal(2)10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂

Compound No. 590: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Thi(2)10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Thi-NH ₂

Compound No. 591: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Tyr10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Tyr-NH ₂

Compound No. 592: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Phe(4F)10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂

Compound No. 594: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Hph10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Hph-NH ₂

Compound No. 595: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Cha10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Cha-NH ₂

Compound No. 596: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Leu10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Leu-NH ₂

Compound No. 597: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 598: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 599: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Orn9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Orn-Trp-NH ₂

Compound No. 600: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂

Compound No. 601: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-Gly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 602: des(1)-Ac-[D-NMeTyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-NMeTyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 603: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Thr-D-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 604: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Tos)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Tos)-Trp-NH ₂

Compound No. 605: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(NO2)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(NO2)-Trp-NH ₂

Compound No. 607: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me2)asym9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me2)asym-Trp-NH ₂

Compound No. 608: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me2)sym9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me2)sym-Trp-NH ₂

Compound No. 609: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Et)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Et)-Trp-NH ₂

Compound No. 610: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys(Me2)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Lys(Me2)-Trp-NH ₂

Compound No. 611: des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 612: des(1)-For-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 613: des(1)-propionyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 614: des(1)-amidino-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Amidino-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 615: des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 616: des(1)-Ac-[D-Ala2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Ala-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 617: des(1)-Ac-[D-Leu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Leu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 618: des(1)-Ac-[D-Phe2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 619: des(1)-Ac-[D-Nal(1)2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Nal(1)-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 620: des(1)-Ac-[D-Nal(2)2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Nal(2)-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 621: des(1)-Ac-[D-Lys2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Lys-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 622: des(1)-Ac-[D-Glu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Glu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 623: des(1)-Ac-[D-Tyr2, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 624: des(1)-Ac-[D-Tyr2, Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 625: des(1)-Ac-[D-Tyr2, D-Ala3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 626: des(1)-Ac-[D-Tyr2, D-Leu3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 627: des(1)-Ac-[D-Tyr2, D-Phe3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 628: des(1)-Ac-[D-Tyr2, D-Thr3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Thr-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 629: des(1)-Ac-[D-Tyr2, D-Lys3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 630: des(1)-Ac-[D-Tyr2, D-Glu3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 631: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Ala6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Ala-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 632: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Leu6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Leu-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 633: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Lys6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Lys-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 634: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Glu6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Glu-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 635: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Pya(4)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Pya(4)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 636: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, NMePhe6, AzaGly7, Arg(Me)9, Typ10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-MePhe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 637: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Typ10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 638: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 639: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys9, Typ10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Lys-Trp-NH ₂

Compound No. 641: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ala8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ala-Arg(Me)-Trp-NH ₂

Compound No. 642: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Val8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Val-Arg(Me)-Trp-NH ₂

Compound No. 643: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Phe8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Phe-Arg(Me)-Trp-NH ₂

Compound No. 644: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ser8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ser-Arg(Me)-Trp-NH ₂

Compound No. 645: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Har9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Har-Trp-NH ₂

Compound No. 646: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Har(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Har(Me)-Trp-NH ₂

Compound No. 647: des(1)-Ac-[D-Tyr2, D-Trp3, Asp4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asp-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 648: [Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 649: Ac-[Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 650: [D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 651: Ac-[D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

Ac-D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 652: pGlu-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

pGlu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 653: des(1)-Ac-[D-Tyr2, D-Trp3, D-Asn4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Trp-D-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 654: des(1)-Ac-[D-Tyr2, D-Trp3, D-Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-D-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 655: des(1)-Ac-[D-Tyr2, D-Trp3, NMeAsn4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-NMeAsn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 656: des(1)-Ac-[D-Tyr2, D-Trp3, NMeSer5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-NMeSer-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 657: des(1)-Ac-[D-Tyr2, Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 658: des(1)-Ac-[D-Tyr2, D-Pya(2)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(2)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 659: des(1)-Ac-[D-Tyr2, D-Trp3, allo-Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-allo-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 660: des(1)-Ac-[D-Tyr2, D-Pya(3)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pya(3)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 661: des(1)-Ac-[D-Tyr2, D-Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 662: des(1)-Ac-[D-Tyr2, Tic3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-Tic-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 663: des(1)-Ac-[D-Trp2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 664: des(1)-Ac-[Tyr2, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 665: des(1-2)-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 666: des(1-2)-Ac-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 667: des(1-2)-hexanoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Hexanoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 668: des(1-2)-cyclohexanecarbonyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Cyclohexanecarbonyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 669: des(1-2)-benzoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Benzoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 670: des(1-2)-3-pyridinepropionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

3-Pyridinepropionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 671: des(1-2)-adipyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Adipyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound ID: des(1)-Ac-[D-Tyr2, NMeTrp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-NMeTrp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 674: des(1-2)-6-aminocaproyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

6-aminocaproyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 675: [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10

Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 676: Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 677: Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Nva8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Nva-Arg(Me)-Trp-NH ₂

Compound No. 678: Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ile8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ile-Arg(Me)-Trp-NH ₂

Compound No. 679: des(1-2)-amidino-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Amidino-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 680: des(1-2)-glycolyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Glycoloyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 681: des(1)-glycoloyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Glycoloyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 682: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Gln8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Gln-Arg(Me)-Trp-NH ₂

Compound No. 685: des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9]MS10

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂

Compound No. 686: des(1)-Ac-[D-Tyr2, D-Trp3, Gly4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Gly-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 688: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Pya(4)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Pya(4)-Trp-NH ₂

Compound No. 689: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, D-Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-D-Trp-NH ₂

Compound No. 691: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Tyr-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 692: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Trp6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Trp-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 693: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr(Me)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Tyr(Me)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 694: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Nal(2)6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Nal(2)-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 695: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Thi6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Thi-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 696: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Cha6, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Cha-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 698: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Abu8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Abu-Arg(Me)-Trp-NH ₂

Compound No. 699: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, γMeLeu8, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-γMeLeu-Arg(Me)-Trp-NH ₂

Compound No. 700: des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Aib8,, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Aib-Arg(Me)-Trp-NH ₂

Compound No. 701: des(1)-Ac-[D-Tyr2, D-Trp3, Dap4, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Dap-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 702: des(1)-Ac-[D-Tyr2, D-Trp3, Asp(NHMe)4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asp(NHMe)-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

Compound No. 703: des(1)-Ac-[D-Tyr2, D-Trp3, Asp(NMe2)4, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10

Ac-D-Tyr-D-Trp-Asp(NMe2)-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂

As for the transferin derivative (II), it is preferred to use a transferin derivative represented by the following formula: XX0-XX2-XX3-XX4-XX5-XX6-AzaGly-XX8-XX9-XX10- _NH

(in:

XX0 represents formyl, C _1-6 alkanoyl (such as acetyl, propionyl, butyryl, hexanoyl, etc.; preferably acetyl, propionyl, butyryl; more preferably acetyl), cyclopropanecarbonyl, 6- (Acetyl-D-arginylamino)hexanoyl, 6-((R)-2,3-diaminopropionylamino)hexanoyl, 6-(D-norleucylamino)hexanoyl, 4- (D-arginylamino)butyryl or 3-(4-hydroxyphenyl)propionyl, glycyl, tyrosyl, acetylglycyl, acetyltyrosyl, D-tyrosyl, acetyl Base-D-tyrosyl, pyroglutamyl, 3-(pyridin-3-yl) propionyl, adipyl or 6-aminocaproyl (preferably acetyl, etc.);

XX2 represents Tyr, D-Tyr, D-Ala, D-Leu, D-Phe, D-Lys, D-Trp or bond arm (preferably D-Tyr or bond arm; more preferably D-Tyr);

XX3 represents Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D-3-pyridylalanine or D-4-pyridylalanine (preferably D-Trp or D-4-pyridylalanine);

XX4 represents Asn, 2-amino-3-ureidopropionic acid, N ^β -formyl diaminopropionic acid or N ^β -acetyl diaminopropionic acid (preferably Asn);

XX5 represents Ser, Thr or Val (preferably Ser or Thr);

XX6 represents Phe, Tyr, Trp, Tyr(Me), Thi, Nal(2), Cha, 4-pyridylalanine or 4-fluorophenylalanine (preferably Phe or 4-fluorophenylalanine) ;

AzaGly means azaglycine;

XX8 represents Leu, Nva or Val (preferably Leu);

XX9 represents Arg, OrnArg(Me) or Arg(symMe2) (preferably Arg(Me));

XX10 represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine (preferably Phe or Trp)), or a salt thereof. More preferably the compound shown in the following compound numbers:

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 550),

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 551),

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 552),

Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 558),

3-(4-hydroxyphenyl)propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 559),

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 562),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 571),

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 579),

Ac-D-Tyr-D-Trp-Dap(For)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 585),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂ (Compound No. 589),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂ (Compound No. 592),

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 612),

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 613),

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 618),

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 627),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 637),

Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 638),

Ac-D-Tyr-D-Pya(2)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 658),

Ac-D-Tyr-D-Pya(3)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 660),

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 663), or a salt thereof.

The transferin derivative (II) or its salt or its prodrug in the present invention has excellent blood stability in addition to the excellent effect of inhibiting cancer metastasis and cancer growth, and can be used for preventing or treating cancer (such as lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, etc.). The transferin derivative (II) or its salt or its prodrug of the present invention has the effect of controlling the function of pancreas, and can be used as a drug for preventing or treating pancreas diseases (such as acute or chronic pancreatitis, pancreatic cancer, etc.). The transferin derivative (II) of the present invention or its salt or its prodrug has the function of controlling the placenta, and can be used for the prevention or treatment of choriocarcinoma, mole, invasive mole, abortion, fetal hypoplasia, glucose Metabolic, dyslipidemia, or labor-inducing drugs.

In addition, the transferin derivative (II) of the present invention or its salt or its prodrug has the effects of increasing sugar level, promoting glucagon secretion and promoting urine production, and can be used for the prevention or treatment of obesity, hyperlipidemia, II type diabetes, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, dysuria, insulin resistance, unstable diabetes, lipoatrophy, insulin allergy, insulinoma, arterial Agents for cirrhosis, thrombotic disease or lipotoxicity.

In addition, the transferin derivative (II) or its salt or its prodrug of the present invention has excellent functions of promoting gonadotropin secretion and sex hormone secretion, including ovulation or stimulating ovulation, and can become a low-toxic and stable drug , such as drugs to improve gonadal function, drugs to prevent or treat hormone-dependent cancers (such as prostate cancer, breast cancer, etc.), infertility, endometriosis, premature puberty, uterine fibroids, etc., to induce or stimulate ovulation Drugs, gonadotropin secretagogues, contraceptives, sex hormone secretagogues, etc.

In addition, the transferin derivative (II) of the present invention or a salt thereof or a prodrug thereof can be used as a drug for preventing or treating Alzheimer's disease, mild cognitive impairment, and the like.

The transferin derivatives (III) [including transferin derivatives (II) and transferin derivatives (I)] or their salts or prodrugs of the present invention can be used as drugs for inhibiting gonadotropin secretion or sex hormone secretion; A down-regulator of gonadotropins or sex hormones; a down-regulator of the OT7T175 (transferin receptor) protein formed by the amino acid sequence shown in SEQ ID NO: 9; for the prevention or treatment of hormone-dependent cancers (such as prostate cancer, breast cancer, etc. ; especially hormone-sensitive prostate cancer, hormone-sensitive prostate cancer, etc.); drugs for the prevention or treatment of endometriosis; drugs that inhibit ovarian follicle maturation; menstrual cycle stoppers; treatment of uterine muscle Drugs for tumors; drugs for the treatment of premature puberty; contraceptives, etc.

In addition, the transferin derivative (III) [including transferin derivative (II) and transferin derivative (I)] of the present invention or a salt thereof or a prodrug thereof can be used as an immunopotentiator (infection prevention agent after myelosuppression, Immunopotentiator against cancer); preventive/therapeutic agent for bulbar muscular atrophy; drug for protecting ovaries; preventive/therapeutic agent for benign prostatic hypertrophy (BPH); preventive/therapeutic agent for gender identity disorder or in vitro fertilization (IVF) preventive/therapeutic agents. In addition, it can also be used as a preventive/therapeutic agent for infertility, hypogonadism, oligospermia, azoospermia, azoospermia, hypospermia, or dead sperm. In addition, it is also useful for diseases such as prostate cancer, uterine cancer, hormone-dependent diseases of breast cancer; such as hypohysialtumor, enlarged prostate, endometriosis, uterine fibroids, precocious puberty , dysmenorrhea, amenorrhea, menstrual syndrome, multilocular ovary syndrome sex hormone-dependent cancer; postoperative recurrence of the above-mentioned cancers; metastasis of the above-mentioned cancers; hypopituitarism; ); menopausal disorders; unspecified diseases; sex hormone-dependent disorders such as abnormal bone calcium and phosphorus metabolism. It can also be used for contraception (or infertility when the rebound effect occurs after stopping the drug).

In addition, transferin itself, DNA encoding transferin, etc. can be used as drugs for inhibiting gonadotropin secretion or sex hormone secretion, gonadotropin or sex hormone down-regulator, human OT7T175 (transferase) formed by the amino acid sequence shown in SEQ ID NO: 9 hormone receptor) protein down-regulators, drugs for the prevention or treatment of hormone-dependent cancers (such as prostate cancer, breast cancer, etc., especially hormone-sensitive prostate cancer, hormone-sensitive prostate cancer, etc.), for the prevention or treatment of intrauterine Drugs for membrane ectopia, drugs for suppressing maturation of ovarian follicles, menstrual cycle stoppers, drugs for treating uterine fibroids, drugs for treating premature puberty, contraceptives, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

The transferin derivatives (I) and (II) of the present invention can be produced by a known method of peptide synthesis. As a method of peptide synthesis, for example, solid-phase synthesis or liquid-phase synthesis can be used. That is, by repeatedly condensing the partial peptide or amino acid that can form the peptide of the present invention and the remaining part, a product having the desired sequence is formed. When the product has a protecting group, the protecting group is removed to form the desired peptide. Known methods for condensation and removal of protecting groups are shown in (i) to (v) below.

(1) M. Bodanszky and M.A. Ondetti: Peptide Synthesis, Interscience Publishers, New York (1966)

(2) Schroeder and Luebke: The Peptide, Academic Press, New York (1965)

(3) Nobuo Izumiya et al.: Peptide Gosei-no-Kiso to Jikken (Basics and experiments of peptide synthesis), published by Maruzen Co. (1975)

(4) Haruaki Yajima and Shunpei Sakakibara: Seikagaku Jikken Koza (Biochemical Experiment) 1, Tanpakushitsu no Kagaku (Chemistry of Proteins) IV, 205 (1977)

(5) Edited by Haruaki Yajima: Zoku Iyakuhin no Kaihatsu (A sequel to Development of Pharmaceuticals), Vol.14, Peptide Synthesis, published by Hirokawa Shoten

After completion of the reaction, the product can be purified and isolated by a combination of conventional purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography, and recrystallization to provide the partial peptides of the present invention. When the peptide obtained by the above method is in a free state, the peptide can be converted into an appropriate salt by a known method; when the obtained protein is in the form of a salt, it can be converted into a free state by a known method.

For the condensation of protected amino acids or peptides, various activating reagents that can be used in protein synthesis can be used, and triphosphonium salts, tetramethyluronium salts, carbodiimides, and the like are particularly preferable. Examples of triphosphonium salts include benzotriazol-1-yloxytris(pyrrolidinium)phosphonium hexafluorophosphate (PyBOP), bromotris(pyrrolidinium)phosphonium hexafluorophosphate (PyBroP), and 7- Azabenzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyAOP); examples of tetramethyluronium salts include 2-(1H-benzotriazol-1-yl)- 1,1,3,3-hexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-hexafluorophosphate (HATU), 2 -(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(5-norbornene-2,3-di Carboxyimino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU) and O-(N-succinimidyl (imidyl))-1,1,3,3-tetrafluoroborate (TNTU) methyluronium tetrafluoroborate (TSTU); examples of carbodiimides include DCC, N,N'-diisopropylcarbodiimide (DIPCDI) and N-ethyl-N'-(3- Dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl) and the like. For condensations using these reagents, it is preferred to add a racemization inhibitor (eg HONB, HOBt, HOAt, HOOBt, etc.). The solvent used in the condensation can be appropriately selected from solvents known to be suitable for condensation. For example, use amides such as anhydrous or aqueous N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc., halogenated hydrocarbons such as dichloromethane, chloroform, etc., alcohols such as Trifluoroethanol, propanol, etc., sulfoxides, such as dimethyl sulfoxide, etc., tertiary amines, such as pyridine, etc., ethers, such as dioxane, tetrahydrofuran, etc., nitriles, such as acetonitrile, propionitrile, etc., esters, such as methyl acetate, Ethyl acetate, etc., or a suitable mixture thereof, etc. The reaction temperature is appropriately selected within the range suitable for the peptide bond forming reaction, usually within the range of about -20°C to 50°C. The activated amino acid derivative is usually used in a 1.5 to 6-fold excess. During solid-phase synthesis, the condensation is investigated by ninhydrin reaction; when the condensation is insufficient, the condensation can be fully carried out by repeating the condensation reaction without removing the protecting group. When the condensation is still insufficient after repeated reactions, use acetic anhydride or acetylimidazole to acylate unreacted amino acids to eliminate adverse effects on subsequent reactions.

Examples of the protecting group for the amino group of the raw amino acid include Z, Boc, tert-amyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, adamantyloxy ylcarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulphenyl (2-nitrophenylsulphenyl), diphenylphosphinothioyl (diphenyphosphinothioyl), 9-fluorenylmethoxycarbonyl (Fmoc ), trityl, _etc. Examples of carboxyl protecting groups _{include allyl} , 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tri Tolylhydrazide, etc.

The hydroxyl groups of serine and threonine can be protected by, for example, esterification or etherification. Examples of groups suitable for esterification include lower carbon ( _C2-4 ) alkanoyl such as acetyl, aroyl such as benzoyl etc. and groups derived from organic acids. Examples of groups suitable for etherification include benzyl, tetrahydropyranyl, tert-butyl, trytyl (Trt), and the like.

Examples of the group protecting the phenolic hydroxyl group of tyrosine include Bzl, Cl ₂ -Bzl, 2-nitrobenzyl, Br-Z, tert-butyl and the like.

Examples of groups protecting the imidazole moiety of histidine include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), DNP, Bom, Bum, Boc, Trt, Fmoc, and the like.

Examples of protecting groups for the guanidine group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS ), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), 1,3,5-trimethylbenzene-2-sulfonyl (Mts), 2,2,4 , 6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO ₂ etc.

Examples of protecting groups for side chain amino acids of lysine include Z, CI-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxcyclohexylene ( Dde) and so on.

Examples of the protecting group of the indole group of tryptophan include formyl (For), Z, Boc, Mts, Mtr and the like.

Protecting groups for asparagine and glutamine include Trt, xanthenyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob )wait.

Examples of activated carboxyl groups in the starting materials include the corresponding anhydrides, azides, activated esters [and alcohols (e.g. pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol phenol, cyanomethanol, p-nitrophenol, HONB, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) ester], etc. As the amino acid whose amino group is activated in the starting material, the corresponding phosphoramide can be used.

In order to remove (separate) the protecting group, there are the following methods, under hydrogen flow, in the presence of a catalyst such as Pd-black or Pd-carbon, carry out a catalytic reduction reaction; with anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, Trifluoroacetic acid, trimethylsilyl bromide (TMSBr), trimethylsilyl triflate, tetrafluoroboric acid, tris(trifluoro)boron, boron tribromide Or their mixed solution is treated with acid; it is treated with diisopropylethylamine, triethylamine, piperidine, piperazine, etc. with alkali; it is reduced with sodium under liquid ammonia. Removal of the protecting group by the above-mentioned acid treatment is generally carried out at a temperature of about -20°C to 40°C. In the acid treatment, add cation scavengers such as anisole, phenol, thioanisole, m-cresol, p-cresol, etc., dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedi Mercaptans and the like are advantageous for processing. In addition, 2,4-dinitrophenyl, which is known as a protecting group of imidazole of histidine, is removed by treating with thiophenol. The formyl group which is the protecting group of indole of tryptophan can be removed by the above-mentioned acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, etc. Alkali such as dilute sodium hydroxide solution and dilute ammonia water can be removed by treatment.

The protection of the functional group that should not be involved in the reaction of the starting material, the protecting group, the removal of the protecting group, and the activation of the functional group involved in the reaction can all be appropriately selected from known groups and known methods.

Another way to obtain amides of peptides, for example, first protect the α-carboxyl group of the carboxy-terminal amino acid by amidation; then extend the peptide chain from the amino side to the required chain length. Thereafter, a peptide (or amino acid) from which only the protecting group of the N-terminal α-amino group of the peptide chain has been removed and a peptide (or amino acid) from which only the protecting group of the C-terminal carboxyl group has been removed is prepared. The two peptides were condensed in the above solvent mixture. Details of the condensation reaction are the same as above. After purification of the protected peptide obtained by condensation, all protecting groups were removed by the method described above to obtain the desired crude peptide. The crude peptide is purified by various known purification methods. Lyophilization of the main fraction yields the amide of the desired peptide.

When the transferin derivatives (I) and (II) of the present invention exist as stereoisomers, diastereomers, conformers, etc., each can be isolated by the above-mentioned separation and purification methods as necessary. In addition, when the compound of the present invention is racemic, it can be separated into S isomer and R isomer by conventional optical resolution methods.

When the transferin derivatives (I) and (II) of the present invention have stereoisomers, the present invention includes cases where these isomers exist alone as well as isomers that exist as a mixture thereof.

In addition, the transferin derivatives (I) and (II) of the present invention may contain water or not.

The transferin derivatives (I) and (II) of the present invention may be labeled with an isotope (eg ³ H, ¹⁴ C, ³⁵ S) or the like.

Peptides appearing in this specification follow the convention that the N-terminus (amino-terminus) is on the left-hand side and the C-terminus (carboxy-terminus) is on the right-hand side. In peptides, the C-terminus is usually in the form of amide (-CONH ₂ ), carboxyl (-COOH), carboxylate (-COO ^- ), alkamide (-CONHR) or ester (-COOR), preferably amide (- CONH ₂ ) form. Examples of R in esters or alkamides include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.; C _3-8 cycloalkyl groups such as cyclopentyl, cyclo Hexyl, etc.; C _6-1 2 aryl such as phenyl, α-naphthyl, etc.; C _7-14 aralkyl, such as phenyl-C _1-2 -alkyl, such as benzyl, phenethyl, etc., or α-naphthyl-C _1-2 -alkyl, such as α-naphthylmethyl, etc.; pivaloyloxymethyl, which is commonly used as an ester for oral use, etc.

Examples of the salt of the transferin derivative (I) of the present invention include metal salts, ammonium salts, salts with organic bases, salts with non-organic acids, salts with organic acids, salts with basic or acidic amino acids and the like. Preferable examples of metal salts include alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; aluminum salts and the like. Preferable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, Amine, N,N'-dibenzylethylenediamine, etc. Preferable examples of salts with non-organic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, acid, p-toluenesulfonic acid, etc. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (such as sodium salts, potassium salts, etc.), alkaline earth metal salts (such as calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc. are preferred. When the compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maric acid, etc. Salts formed from toric acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

The prodrug of the transferin derivative (III) or a salt thereof (hereinafter, sometimes simply referred to as the transferin derivative (III) of the present invention) refers to a transferin derivative that is effective under physiological conditions in a living body. Or it can be transformed into the transferin derivative (III) of the present invention due to the reaction of enzymes, gastric acid, etc. That is to say, the prodrug of the present invention is a transferin derivative, which is transformed into the transferin derivative (III) of the present invention by enzymatic oxidation, reduction, hydrolysis, etc., or transformed into the present invention's Transferin derivatives (III).

The prodrug of the transferin derivative (I) or its salt of the present invention (hereinafter sometimes simply referred to as the transferin derivative (I) of the present invention) used, and the transferin derivative (II) of the present invention or The prodrug of its salt (hereinafter sometimes simply referred to as the transferin derivative (II) of the present invention) is the same as the prodrug described for the transferin derivative (III) of the present invention.

The prodrug of the transferin derivative (III) of the present invention includes a transferin derivative, wherein the amino group in the transferin derivative (III) of the present invention is substituted by an acyl group, an alkyl group, a phosphoric acid, etc. (for example, a transferin derivative, Wherein the amino group in the transferin derivative (III) of the present invention is replaced by eicosyl, alanyl, pentylaminocarbonyl (5-methyl-2-oxo-1,3-dioxole- 4-yl) methoxycarbonyl, tetrahydrofuranyl, pyrrolidinylmethyl, pivaloyloxymethyl, tert-butyl, etc. substituted); transferin derivatives, wherein the hydroxyl group of the transferin derivatives (I) of the present invention Substituted by acyl, alkyl, phosphoric acid, boronic acid, etc. (for example, transferin derivatives, wherein the hydroxyl group of the transferin derivative (III) of the present invention is replaced by acetyl, palmitoyl, propionyl, pivaloyl, succinyl, rich Malyl, alanyl, dimethylaminomethylcarbonyl, etc. substituted); and transferin derivatives, wherein the carboxyl group of the transferin derivative (III) of the present invention is substituted by ester, amide, etc. (for example, transferin derivatives, Among them, the carboxyl group of the transferin derivative (III) of the present invention is replaced by ethyl ester, phenyl ester, carbonyl methyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxy Ethyl ester, Phthalyl ester, (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, Cyclohexyloxycarbonyl ethyl ester, Methylamide etc. to replace) etc. These transferin derivatives can be produced from the transferin derivative (I) of the present invention by the above-mentioned known methods.

The prodrugs of the transferin derivative (III) of the present invention may also be those prodrugs that are converted into the transferin derivative (III) of the present invention under physiological conditions as described in: "Pharmaceutical Research and Development", Vol.7 (Drug design), pp. 163-198, published by Hirokawa Publishing Co in 1990.

The transferin derivatives (I), (II) or (III) of the present invention or their salts or their prodrugs (hereinafter, sometimes simply referred to as compounds of the present invention) have the activity of inhibiting cancer metastasis or inhibiting cancer growth. active. Transferin derivatives are therefore useful for pharmaceutical preparations for the prophylaxis or treatment of all cancers (e.g. lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer cancer, etc.) drugs.

The compound of the present invention also has the function of controlling pancreas function, and as a drug for controlling pancreas function, it can be used as a drug for preventing or treating various pancreatic diseases (such as acute or chronic pancreatitis, pancreatic cancer, etc.).

The compound of the present invention also has the effect of controlling placental function, as a drug for controlling placental function, it can be used for preventing or treating choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or Drugs for labor induction.

In addition, the compound of the present invention has the effects of increasing sugar level, promoting glucagon secretion and promoting urine production, so it can be used as a drug for increasing blood sugar, a glucagon secretion promoting agent and a urine production promoting agent for the prevention or treatment of obesity, Hyperlipidemia, type II diabetes, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, dysuria, insulin resistance, unstable diabetes, fatty atrophy, Drugs for insulin allergy, insulinoma, arteriosclerosis, thrombotic disease or lipotoxicity are useful.

In addition, the compounds of the present invention also have the functions of promoting the secretion of gonadotropins (such as FSH, LH, etc.), promoting sex hormones [such as androgens (such as testosterone, androstenedione, etc.), etc.), progesterone, etc.] secretion, improving gonadal function, inducing or stimulating ovulation, and sexual maturation, etc., so it can be used as a drug for improving gonadal function, a drug for inducing or stimulating ovulation, a gonadotropin secretagogue or a sex hormone Secretagogues, or prophylaxis or treatment of hormone-dependent cancers [eg, prostate cancer, breast cancer, etc.], infertility [eg, irregular menstruation, dysmenorrhea, amenorrhea, amenorrhea due to weight loss, secondary amenorrhea, anovulation , ovarian hypofunction, hypogonadism, spermatogenesis disorder, hypogonadism (such as impotence, etc.), genital atrophy, testicular atrophy, testicular dysfunction, sperm deficiency, androgen deficiency (hypoandrogenemia), etc.], endometriosis , premature puberty, uterine fibroids and other drugs.

In addition, the prodrugs of the transferin derivatives (I) or (II) or their salts of the present invention can be used as drugs for the prevention or treatment of Alzheimer's disease, mild cognitive impairment and the like.

In addition, the compounds of the present invention have superior blood stability compared to natural transferins, such as transferins 54(1-54) or transferins 10(45-54).

The transferin derivatives (III) [including transferin derivatives (II) and transferin derivatives (I)] of the present invention or their salts or prodrugs are useful as drugs for inhibiting gonadotropin secretion or sex hormone secretion drugs; downregulators of gonadotropins (eg, FSH, LH) or sex hormones [eg, androgens (eg, testosterone, androstenedione), estrogens (eg, estradiol, estrone), progesterone]; especially , by down-regulating gonadotropin or sex hormone (wherein, down-regulating gonadotropin or sex hormone can be the pulsation (pulse) reduction of LHRH or the depletion of LHRH), or down-regulating people OT7T175 (transfer hormone receptor) protein, drugs that inhibit gonadotropin secretion or sex hormone secretion; drugs that prevent or treat hormone-dependent cancers (such as prostate cancer, breast cancer, etc., especially hormone-sensitive prostate cancer, hormone-sensitive prostate cancer, etc.) ; drugs to prevent or treat endometriosis; drugs to inhibit ovarian follicle maturation; menstrual cycle stoppers; drugs to treat uterine fibroids; drugs to treat premature puberty;

When the transferin derivatives (III) [including transferin derivatives (II) and transferin derivatives (I)] of the present invention or their salts or prodrugs, transferin itself or DNA encoding transferin, etc. have the usual agonistic When the drug is active, the transferin derivatives are present in a dose much greater than the indicated dose by administering an effective dose sufficient to inhibit the secretion of gonadotropins or sex hormones at the site or tissue where the therapeutic effect is to be exhibited. Requirements for inhibiting gonadotropin secretion or sex hormone secretion (that is, the dose of transferred transferin derivatives administered is greater than the normal effective dose, at which transferin derivatives show the effect of inhibiting cancer metastasis, inhibiting cancer growth, etc.; or play a role in promoting Gonadal hormone secretagogues, promoting the secretion of sex hormones, etc.). Specific examples include continuous or continuous administration of normal effective doses (including administration techniques for gradual release of pharmaceutical ingredients by bolus administration), and the like. In addition, when the transferin derivative (III) of the present invention [including transferin derivative (II) and transferin derivative (I)] or a salt thereof or a prodrug thereof, etc. have sufficient agonist activity greater than necessary ( superagonist activity), then the site or tissue where therapeutic effect is desired will be maintained at an activity greater than that exhibited at the required dose. Therefore, even if it is administered at a dose normally effective for suppressing the secretion of gonadotropins or sex hormones, a sufficient effect of suppressing secretion of gonadotropins or sex hormones can be obtained.

That is, administration of the transferin derivative (III) [including transferin derivative (II) and transferin derivative (I)] or a salt or prodrug thereof is administered in an effective amount sufficient for inhibiting gonadotropins or sex hormones , or transferin itself, DNA encoding transferin, etc. Therefore, it may exist in a dose greater than the required amount in the site or tissue where the drug effect is required, or to maintain the active transferin derivatives with an activity greater than the required amount, resulting in inhibition of gonadotropin secretion or sex hormone secretion. Effect.

The pharmaceutical compositions containing the compounds of the present invention have low toxicity and can therefore be safely administered orally or parenterally (e.g. topically, rectally, intravenously, etc.), or directly in the original form or in the form of pharmaceutical preparations, such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquid preparations, injections, suppositories, sustained-release preparations, etc.

In the pharmaceutical preparation of the present invention, the compound of the present invention is contained in an amount of about 0.01 to about 100 wt % based on the total weight of the preparation.

The dosage of the compound of the present invention varies according to the subject of administration, target organ, disease and route of administration, etc. When taken orally, the compound is usually in the range of about 0.1 to about 100 mg per day, preferably about 1.0 to about 50 mg, more preferably Doses of about 1.0 to about 20 mg are administered to cancer patients (when the body weight is 60 kg). In the case of parenteral administration, the single dose of the compound varies depending on the administration object, target organ, disease and administration route, etc., and when it is in the form of injection, it is beneficial that it is usually about 0.01 to 30 mg per day, Preferably a dose of about 0.1 to about 20 mg, more preferably about 0.1 to about 10 mg is administered to a cancer patient (when the body weight is 60 kg). For other animals, equivalent doses per 60 kg body weight can be administered.

The pharmacologically acceptable carrier that can be used in the preparation of the pharmaceutical preparation of the present invention includes various organic or inorganic carrier substances commonly used as materials in pharmaceutical preparation. These substances include, for example, excipients, lubricants, binders, and disintegrants in solid formulations, solvents, dissolution aids, suspending agents, isotonic agents, buffers, placebos in liquid formulations wait. In addition, commonly used additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, humectants, etc. can be added in appropriate doses as needed.

Examples of excipients include, for example, lactose, saccharose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.

Examples of lubricants used include, for example, magnesium stearate, calcium stearate, talc, colloidal silicon dioxide, and the like.

Examples of the binder include, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin , methyl cellulose, sodium carboxymethyl cellulose, etc.

Examples of disintegrants include, for example, starch, carboxymethylcellulose, carmellose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.

Examples of solvents include, for example, water for injection, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and the like.

Examples of solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, mono Glyceryl stearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc. .

Examples of isotonic agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

Examples of buffers include, for example, buffer solutions of phosphate, acetate, carbonate, citrate, and the like.

Examples of placebos include, for example, benzyl alcohol and the like.

Examples of preservatives include, for example, p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, deshydroacetic acid, sorbic acid, and the like.

Examples of antioxidants include, for example, sulfites, ascorbic acid, alpha-tocopherol, and the like.

In addition, the compound of the present invention can also be combined with drugs other than the compound of the present invention.

Examples of drugs that can be combined with the compound of the present invention (hereinafter referred to as combination drugs) include, for example, chemotherapeutic agents, hormone therapeutic agents, immunotherapeutic agents and the like for treating cancer.

"Chemotherapeutic agents" include, for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents.

Examples of "alkylating agents" include, for example, nitrogen mustard, nitrogen mustard-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquinone, toluenesulfonic acid Improsulfan, busulfan, nimustine hydrochloride, dibromomannitol, rnelphalan, dacarbazine, ramustine, estramustine sodium phosphate, triethylenemelamine, carboxylate Mustin, lomustine, streptozocin, pipobromane, etoglu, carboplatin, cisplatin, mipa, nedaplatin, oxaliplatin, hexamethylmelamine, amustine, hydrochloric acid Dibrospidium hydrochloride, fomustine, prednimustine, purine tepa, ribomustin, temozolomide, treosulphan, cyclophosphamide, net division Statin stimulant (zinostatin stimalamer), carboquinone, adolaisine, cysteamine nitrosourea, bizelesine, etc.

Examples of "anti-metabolic agents" include, for example, mercaptopurine, 6-mercaptopurine inosine, mercaptopurine, methotrexate, enoxitabine, cytarabine, cytarabine ocfosfate, ancetin hydrochloride Tabine, 5-FU drugs (such as fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur, etc.), aminopterin, Leucovorin calcium, tabloid, thiopurine, folinatecalcium, leucovorin calcium, cladribine, etimetidine, fludarabine, gemcitabine, carbamoyl Hydroxylamine, Pentostatin, Pitrexine, Iodine Glycoside, Mitoguanidine Hydrazone, Thiazophrine, Amustine, etc.

Examples of "anticancer antibiotics" include, for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pelomycin sulfate, Daunorubicin hydrochloride, clonidine hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarcinstatin, shimitromycin, sarcomamycin, carcinophilin, mitotane, Zorrubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, etc.

Examples of the "plant-derived anticancer agent" include, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, etc. .

Examples of "hormone therapy agents" include, for example, fosestrol, diethylstylbestrol, chlorphenestrol, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyprochlor acetate Megestrol, danazol, allylestradiol, gestrinone, mepatrexine, raloxifene, omexifen, levomeloxifene, anti-estrogens (e.g., tamoxifen citrate oxifene, toremifene citrate, etc.), pill preparations, mexandane, testrolactone, aminoglutethimide, LH-RH antagonists (such as goserelin acetate, buserelin, leuprolide, etc.), droloxifene, thiosterol, ethinylestradiol sulfate, aromatase inhibitors (such as fadrozole hydrochloride, anastrozole, retrozole, exemestane, vorozole, formestane, etc.), anti-androgens (such as flutamide, bicartamide, nilutamide, etc.), 5α-reductase inhibitors (such as finasteride, epletamide, etc.) special class), corticotropic hormone drugs (such as dexamethasone, prednisolone, betamethasone, triamcinolone acetonide, etc.), androgen synthesis inhibitors (such as abiraterone, etc.), retinoic acid (retinoid) and delayed vitamin Drugs for formic acid metabolism (such as riazol, etc.), among which LH-RH antagonists (such as goserelin acetate, buserelin, leuprolide, etc.) are preferred.

Examples of "immunotherapeutic agents (BRM)" include, for example, picibanil, krestin, sizoran, lentinan, ubenimex, interferon, interleukin, -macrophage Colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG, Corynebacterium pumilus, levamisole, Yunzhi polysaccharide K (polysaccharide K), procodazole, etc.

The combined use of the compound of the present invention and a combination drug can bring about the following excellent effects, for example.

(1) The dose of the compound of the present invention is reduced compared to the dose administered alone.

(2) Drugs to be used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.).

(3) Combination drugs whose action mechanism is different from that of the compound of the present invention can be selected, so the treatment period can be extended.

(4) Combination drugs whose action mechanism is different from that of the compound of the present invention can be selected, so that a long-lasting therapeutic effect can be obtained.

(5) A synergistic effect can be obtained by using the compound of the present invention in combination with a combination drug.

In addition, the compounds of the invention can reduce testosterone levels to castrate levels after drug treatment. Therefore, combination drugs, such as LH-RH antagonists (such as goserelin acetate, buserelin, leuprolide, etc., preferably leuprolide) are used in combination with the compounds of the present invention, and can be used in the present invention. Drug treatment with compounds of the compounds rapidly decreased testosterone levels to castrate levels. In addition, since combination drugs, such as LH-RH antagonists (such as goserelin acetate, buserelin, leuprolide, etc., preferably leuprolide) are used in combination with the compound of the present invention, prolonged During maintenance of hormone dependence, it is therefore advantageous to use combination drugs in combination with the compounds of the invention.

Hereinafter, the combined use of the compound (I) of the present invention and a combination drug is referred to as "combined preparation of the present invention".

When using the combined preparation of the present invention, there is no particular limitation on the administration period of the compound of the present invention and the combined drug; the compound of the present invention or its pharmaceutical composition and the combined drug or its pharmaceutical composition can be administered simultaneously or at intervals Administer the drug to the subject for a certain period of time. The dose of the combination drug can be adjusted according to the clinical dose, and can also be adjusted appropriately according to the administration object, administration route, disease, combination and other conditions.

The administration method of the concomitant agent of the present invention is not particularly limited, as long as the compound of the present invention is used in combination with the concomitant drug at the time of administration. For such administration methods, there are, for example, (1) administration of a single preparation obtained by simultaneously mixing the compound of the present invention and a combination drug, (2) simultaneous administration of the compound of the present invention and a combination drug in the same administration route. Two preparations prepared separately from the drug for the combination, (3) administering the two preparations prepared by the compound of the present invention and the drug for the combination with the same route of administration at a certain time interval, (4) with Different routes of administration, simultaneously administering two kinds of preparations prepared from the compound of the present invention and the combined drug, (5) using different routes of administration, administering at a certain time interval (for example, according to the present invention The compound and the combination drug are administered sequentially, or the reverse order is administered) two preparations prepared separately from the compound of the present invention and the combination drug, etc.

The combination preparation of the present invention has low toxicity, so it can be safely administered orally or parenterally (such as topical, rectal, intravenous administration, etc.), or administered in the original form or in the form of pharmaceutical preparations, such as tablets (including sugar-coated tablets and film-coated tablets). Tablets), powders, granules, capsules (including soft capsules), liquid preparations, injections, suppositories, sustained-release preparations, etc., which are composed of the above-mentioned compounds of the present invention or (and) combinations with pharmaceuticals and pharmacologically acceptable carriers Get mixed. Injections can be injected intravenously, intramuscularly or subcutaneously, and can be administered to organs or directly to lesions.

The pharmacologically acceptable carrier used in the preparation of the combination preparation of the present invention includes various organic or inorganic carrier substances conventionally used as materials in pharmaceutical preparations. These substances include, for example, excipients, lubricants, binders, and disintegrants in solid preparations, and solvents, solubilizers, suspending agents, isotonic agents, buffers, placebos, etc. in liquid preparations. In addition, commonly used additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, humectants, etc. can be added in appropriate doses as needed.

Examples of excipients include, for example, lactose, saccharose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.

Examples of lubricants used include, for example, magnesium stearate, calcium stearate, talc, colloidal silicon dioxide, and the like.

Examples of the binder include, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin , methyl cellulose, sodium carboxymethyl cellulose, etc.

Examples of disintegrants include, for example, starch, carboxymethylcellulose, carmellose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.

Examples of solvents include, for example, water for injection, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and the like.

Examples of solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl allanate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate Esters, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.

Examples of isotonic agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

Examples of buffers include, for example, buffer solutions of phosphate, acetate, carbonate, citrate, and the like.

Examples of placebos include, for example, benzyl alcohol and the like.

Examples of preservatives include, for example, p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, deshydroacetic acid, sorbic acid, and the like.

Examples of antioxidants include, for example, sulfites, ascorbic acid, alpha-tocopherol, and the like.

In the combined preparation of the present invention, the ratio of the compound of the present invention to the combined drug can be appropriately selected according to the subject of administration, administration route, disease, combination, and the like.

For example, the content of the compound of the present invention in the combined preparation of the present invention varies depending on the preparation form of the drug, and is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the total weight of the preparation. , more preferably about 0.5 to 20% by weight.

The content of the combination drug of the present invention in the combination preparation of the present invention varies depending on the preparation form of the drug, and is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.1 to 50% by weight relative to the total weight of the preparation. Preferably it is about 0.5 to 20% by weight.

The content of the additive of the present invention in the combined preparation of the present invention varies depending on the preparation form of the drug, and is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight based on the total weight of the preparation.

When the compound of the present invention and the drug for combination are prepared separately, the content thereof may be the same.

These formulations can be prepared by conventional methods known per se.

For example, by dissolving the compound of the present invention or the combined drug in a dispersant (such as Tween 80 (manufactured by Atlas Powder Company, USA), HCO60 (manufactured by Nikko Chemicals Co., Ltd.), polyethylene glycol, carboxy methylcellulose, sodium alginate, etc.), stabilizers (such as ascorbic acid, sodium metabisulfite), surfactants (such as polysorbate 80, polyethylene glycol, etc.), solubilizers (such as glycerin, ethanol, etc.), buffering agents (such as phosphoric acid or its alkali metal salt, citric acid or its alkali metal salt, etc.), isotonic agent (such as sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulator (such as hydrochloric acid, sodium hydroxide, etc.), preservatives (such as ethyl p-hydroxybenzoate, benzoic acid, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, etc.), solubilizers (such as concentrated glycerin, meglumine etc.), cosolvents (such as propylene glycol, sucrose (saccharose), etc.), placebos (such as glucose, benzyl alcohol, etc.), vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, etc., dissolved and suspended in cosolvents such as propylene glycol, etc. Or emulsified to form oily injections to make injections.

Oral preparations can be prepared by adding the compound of the present invention or the combined drug to the following excipients by conventional methods, for example, excipients (such as lactose, sucrose (saccharose), starch, etc.), disintegrants (such as starch, calcium carbonate, etc.) etc.), binders (such as starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.), lubricants (such as talc, magnesium stearate, polyethylene glycol 6000, etc.) and For other additives, the obtained mixture is compression-molded, and then, if necessary, for taste-masking, enteric-coating or sustained-release purposes, the compression-molded product is coated by a known method to prepare an oral preparation. Coating agents for this purpose include, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyethylene glycol, Tween 80, Prulonic F68, phthalate Cellulose acetate formate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragits (manufactured by Rohm Company, Germany, methacrylic acid/acrylic acid copolymer), and dyes (such as iron oxide, Titanium dioxide). Oral formulations can be formulated as immediate or sustained release forms.

For example, in a suppository, the compound of the present invention or the combination drug can be formulated into an oily or aqueous solid, semi-solid or liquid composition according to a method known per se. The oil base used for the manufacture of the above composition includes glycerides of higher fatty acids [such as cocoa butter, uitepsols (made by Dynamite Nobel Company, Germany) etc.], intermediate fatty acids [such as miglyols (made by Dynamite Nobel Company, Germany) etc.], vegetable oils (such as sesame oil, soybean oil, cottonseed oil, etc.), etc. Aqueous bases include, for example, polyethylene glycol and propylene glycol. Bases for aqueous gels include, for example, natural rubber, cellulose derivatives, vinyl polymers, acrylic polymers, and the like.

The above-mentioned sustained-release preparation forms include sustained-release microcapsules and the like.

Sustained-release microcapsules can be obtained by methods known per se, and are preferably prepared and administered as, for example, a sustained-release preparation shown in the following method [2].

Preferably, the compound of the present invention is formulated for oral administration such as solid preparation (eg powder, granule, tablet, capsule) etc., or for rectal administration such as suppository and the like. Particularly preferred are oral administration forms.

Combination drugs can be prepared in the above dosage forms according to the types of drugs.

The following is about [1] the injection of the compound of the present invention or the combination drug and its preparation, [2] the sustained-release or immediate-release preparation of the compound of the present invention or the combination drug and its preparation, and [3] the compound of the present invention Sublingual formulations, buccal formulations or orally rapidly disintegrating formulations or combination medications and specific instructions on all aspects of their preparation.

[1] Injection and its preparation

Injections are preferably prepared by dissolving the compound of the present invention or the combination drug in water. The injection may contain benzoate and/or salicylate.

Said injection is obtained by dissolving the compound of the present invention or the combination drug and optionally benzoate and/or salicylate in water.

Examples of the above-mentioned benzoate and/or salicylate include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, ammonium salts, meglumine salts, organic salts such as amino Butanetriol and so on.

The concentration of the compound of the present invention or the combination drug in the injection is about 0.5 to 50 w/v%, preferably about 3 to 20 w/v%. The concentration of benzoate and/or salicylate is 0.5 to 50 w/v%, preferably 3 to 20 w/v%.

In addition, commonly used additives for the preparation of injections can be appropriately added to the injection, such as stabilizers (ascorbic acid, sodium metabisulfite, etc.), surfactants (polysorbate 80, polyethylene glycol, etc.), solubilizers, etc. (glycerol, ethanol, etc.), buffering agent (phosphoric acid and its alkali metal salt, citric acid and its alkali metal salt, etc.), isotonic agent (sodium chloride, potassium chloride, etc.), dispersant (hydroxypropyl methylcellulose, etc.) dextrin), pH regulator (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl p-hydroxybenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol , sucrose (saccharose), etc.), placebo (glucose, benzyl alcohol, etc.). These additives are used in proportions usually used in injections.

The pH of the injection is adjusted to 2 to 12, preferably 2.5 to 8.0, by adding a pH adjuster.

The injection is obtained by dissolving the compound of the present invention or combination drug and optionally benzoate and/or salicylate in water, and the above-mentioned additives as needed. These components may be dissolved in any order according to the conventional injection preparation method.

Preferably, the aqueous solution for injection is warmed and used for the preparation of injections after filtration sterilization with a filter or autoclaving in the same manner as usual injections.

The aqueous solution for injection is preferably autoclaved, for example, at 100 to 121°C for 5 to 30 minutes.

In addition, in order to be used as a multiple dosage form individual dosing (multiple dosage form individual dosing), the preparation may also be in the form of a solution having antibacterial activity.

[2] Sustained-release or immediate-release preparations and their preparation

A preferred sustained-release formulation comprises a core containing the compound of the present invention or combination drug, optionally coated with a water-insoluble substance or a swelling polymer. For example, a sustained-release formulation for oral administration that is administered once a day is preferable.

Water-insoluble materials used in coating agents include cellulose ethers such as ethyl cellulose, butyl cellulose, etc., cellulose esters such as cellulose acetate, cellulose propionate, etc., polyvinyl esters such as polyvinyl acetate ester, polyvinyl butyrate, etc., acrylic copolymers such as acrylic acid/methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate/cinnamoethyl methacrylate methacrylate)/aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, alkylamide methacrylate copolymer, poly(methyl methacrylate), polymethacrylate, aminoalkyl methacrylate Ester copolymer, poly(methacrylic anhydride), glycidyl methacrylate copolymer, etc., especially Eudragits series (Rohm & Pharma), such as Eudragit RS-100, RL-100, RS-30D, RL-30D, RL -PO, RS-PO (ethyl acrylate/methyl methacrylate/chlorotrimethyl methacrylate/ethylammonium copolymer) and Eudragit NE-30D (methyl methacrylate/ethyl acrylate copolymer) etc., hydrogenated oils such as hydrogenated sesame oil (such as LUBRI WAX (Freund Industrial Co., Ltd.), etc.), waxes such as palm wax, fatty acid glycerides, paraffin wax, etc., polyfatty acid glycerides, etc.

The swelling polymer is preferably a polymer having acid-removable groups and exhibiting pH-dependent swelling, preferably a polymer having acid-removable groups, such that the polymer having acid-removable groups in the stomach The swelling is small at the acidic pH of the small intestine, and the swelling is large at the neutral pH of the small or large intestine.

Examples of polymers having acidic removable groups and exhibiting pH-dependent swelling include crosslinked polyacrylic acid polymers such as Carbomers 934P, 940, 941, 974P, 980, 1342, etc., polyacrylic acid polymers polycarbophil and calcium polycarbophil (both manufactured by BF Goodrich Chemicals), Hivis Wakos 103, 104, 105 and 304 (all manufactured by Wako Pure Chemical Industries, Ltd.), and the like.

Coating agents used in sustained-release preparations may also contain hydrophilic materials.

Examples of hydrophilic materials include polysaccharides that may have sulfate groups such as pullulan, dextrin, alkali metal alginates, etc., polysaccharides with hydroxyalkyl groups or carboxyalkyl groups such as hydroxypropylcellulose, Hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc., methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, etc.

The content of the water-insoluble material in the coating agent of the sustained-release preparation is about 30 to about 90% (w/w), preferably about 35 to about 80% (w/w), more preferably about 40 to about 75% (w/w), the content of the swelling polymer is about 3 to about 30% (w/w), preferably about 3 to about 15% (w/w). The coating agent may also contain a hydrophilic material, and the content of the hydrophilic material in the coating agent is about 50% (w/w) or less, preferably about 5 to about 40% ( w/w), more preferably from about 5 to about 35% (w/w). Here, the % (w/w) used above is based on the weight % of the coating agent composition remaining after removing all solvents (such as water, lower alcohols such as methanol, ethanol, etc.) from the coating agent solution. .

Sustained-release preparations can be prepared by preparing a core containing the drug shown below, and coating the core with a coating agent solution obtained by heating and melting a water-insoluble material or a swelling polymer or allowing it to Dissolve or disperse in solvents.

I. Preparation of Drug-Containing Cores

The shape of the drug-containing core (hereinafter, sometimes simply referred to as the core) coated with the coating agent is not particularly limited, and is preferably granular, such as granules or fine particles.

When the core is a particle or fine particle, it preferably has an average particle diameter of about 150 to about 2000 μm, more preferably about 500 to about 1400 μm.

Preparation of the core can be carried out by a customary method. For example, the drug is mixed with appropriate excipients, binders, disintegrants, lubricants, stabilizers, etc., and then prepared by wet extrusion granulation, fluidized bed granulation, etc.

The content of the drug in the core is about 0.5 to about 95% (w/w), preferably about 5.0 to about 80% (w/w), more preferably about 30 to about 70% (w/w).

Examples of excipients contained in the core include sugars assaccharose, lactose, mannitol, glucose and the like, starch, crystalline cellulose, calcium phosphate, cornstarch and the like. Among them, crystalline cellulose and corn starch are preferred.

Examples of binders used include polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, Pluronic F68, acacia, gelatin, starch and the like. Examples of disintegrants include carmellose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), crospovidone (crospovidone), low-substituted hydroxypropyl cellulose prime (L-HPC) and so on. Among them, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable. Examples of lubricants and anticoagulation agents include talc, magnesium stearate and inorganic salts thereof, and examples of lubricants include polyethylene glycol and the like. Examples of stabilizers include acids such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid.

In addition to the above-mentioned preparation methods, the core can also be prepared by other methods, such as tumbling granulation technique (tumbling granulation technique), coater coating method, fluidized bed coating method and melt granulation method, wherein, While spraying a binder dissolved in a suitable solvent such as water, lower alcohol (such as methanol, ethanol, etc.) on the inert carrier particles that become the core seed, add the drug or drug and excipient, lubricant, etc. in batches mixture. Examples of inert carrier particles include particles made of saccharose, lactose, starch, crystalline cellulose, and wax, and the carrier preferably has an average particle diameter of about 100 μm to about 1500 μm.

In order to separate the drug in the core from the coating agent, the surface of the core may be coated with a protective material. Examples of protective materials include the aforementioned hydrophilic materials and water-insoluble materials. Preferably, the protective material is polyethylene glycol or a polysaccharide with hydroxyalkyl or carboxyalkyl, more preferably hydroxypropylmethylcellulose and hydroxypropylcellulose. The protective material may contain acids such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid as stabilizers, and talc as a lubricant. When a protective agent is used, its coating amount is about 1 to about 15% (w/w), preferably about 1 to about 10% (w/w), more preferably about 2 to about 8% (w/w), based on the core. /w).

The protective material can be coated by a common coating method, specifically, the core can be spray-coated with the protective material by, for example, a fluidized bed coating method, a clothes pan coating method, and the like.

II. Coating the core with a coating agent

The core obtained above is coated with a coating agent solution to obtain a sustained-release preparation, and the coating agent solution is obtained by melting and heating the above-mentioned water-insoluble material, pH-dependent swelling polymer and hydrophilic material, or by dissolving it in a solvent obtained by dissolving or dispersing.

As a method of coating a core with a coating agent solution, spray coating etc. are mentioned, for example.

In the coating agent solution, the compositional ratio of the water-insoluble material, the swelling polymer, and the hydrophilic material can be appropriately selected so as to be within the content of each component in the coating.

The amount of coating agent is about 1 to about 90% (w/w), preferably about 5 to about 50% (w/w), more preferably about 5 to about 35% (w/w) based on the core (not including coatings of protective materials).

As the solvent of the coating agent solution, water and an organic solvent may be used alone or in combination. When a mixture is used, the ratio of water and organic solvent (water/organic solvent: weight ratio) may vary in the range of 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it can dissolve the water-insoluble material, and examples of the solvent include lower alcohols such as methanol, ethanol, isopropyl alcohol, n-butyl alcohol, alkanones such as acetone, acetonitrile, chloroform, methylene chloride wait. Among them, lower alcohols are preferred, and ethanol and isopropanol are more preferred. Water and mixtures of water and organic solvents are preferred as solvents for coating agent solutions. At this time, in order to stabilize the coating agent solution, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, or maleic acid may be added to the coating agent solution as necessary.

When coating by the spray coating method, it can implement by a usual coating method. Specifically, the core is sprayed with a coating agent solution by a fluidized bed coating method, a coat pan coating method, or the like. Lubricants such as talc, titanium oxide, magnesium stearate, calcium stearate, light silicic anhydride, fatty acid glycerides, hydrogenated sesame oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. can also be added at this time. plasticizer.

After coating with a coating agent, an antistatic agent such as talc may be added as needed.

Immediate release preparations can be liquid (solution, suspension, emulsion, etc.) or solid (granules, pills, tablets, etc.). Oral formulations and parenteral formulations such as injections can be used, and oral formulations are preferred.

Immediate release preparations usually contain, in addition to the drug as the active ingredient, carriers, additives and excipients commonly used in the field of preparations (hereinafter, sometimes referred to as excipients for short). As long as the pharmaceutical adjuvant is a commonly used adjuvant in the preparation field, there is no particular limitation on it. Examples of excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Avicel PH101, manufactured by Asahi Kasei Corporation, etc.), powdered sugar, granulated sugar, mannitol, light silicic anhydride, magnesium carbonate, calcium carbonate, L- cysteine, etc., preferably corn starch and mannitol. All these excipients can be used alone or in combination with others. The content of excipients is based on the total weight of the immediate release preparation, for example, about 4.5 to about 99.4w/w%, preferably about 20 to about 98.5w/w%, more preferably about 30 to about 97w/w%.

The content of the drug in the immediate-release preparation can be appropriately selected in the range of about 0.5% to about 95%, preferably about 1% to about 60%, based on the total weight of the immediate-release preparation.

When the immediate-release preparation is an oral solid preparation, the preparation also contains a disintegrant in addition to the above ingredients. Examples of disintegrants include calcium carboxymethylcellulose (ECG505, manufactured by GOTOKU CHEMICAL Co., Ltd.), croscarmellose sodium (such as Ac-Di-Sol, manufactured by AsahiKasei Corporation), crospovidone (for example, COLIDON CL, manufactured by BASF), low-substituted hydroxypropyl cellulose (Shin-Etsu chemical Co., Ltd.), carboxymethyl starch (MATSUTANI CHEMICAL INDUSTRY Co., Ltd.), sodium carboxymethyl starch (EXORITAB, manufactured by KIMURA SANGYO), partial α-starch (PCS, manufactured by Asahi Kasei Corporation), etc., such as a disintegrant that absorbs water after contact with water, swells or when the active ingredient including the core is mixed with the excipient used Small channels are formed between the agents, causing the particles to disintegrate. All disintegrants can be used alone or in combination with others. The amount of the disintegrant to be used can be appropriately selected according to the kind and amount of the drug used and the special formulation design for release. For example, the amount is about 0.05 to about 30 w/w%, preferably about 0.5 to about 15 w/w%, based on the total weight of the immediate release preparation.

When the immediate-release preparation is an oral solid preparation, the preparation may optionally contain additives commonly used in solid preparations in addition to the above ingredients. Examples of additives include binders (such as sucrose, gelatin, powdered gum arabic, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, (pullran, dextrin, etc.), lubricants (polyethylene glycol, magnesium stearate, talc, light silicic anhydrides (e.g., aerosil (NIPPONAEROSIL)), surfactants (e.g., anionic surface Active agents, such as sodium alkyl sulfate; nonionic surfactants, such as polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.), colorants (such as tar-based Coloring agent, caramel, red iron, titanium oxide, riboflavin), can also add flavoring agents (such as sweeteners, spices, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. as required. In addition Organic acids such as tartaric acid, citric acid, succinic acid, and fumaric acid can also be added as stabilizers.

As the binder, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone, and the like are preferable.

Immediate-release preparations can be prepared by mixing the above-mentioned components, kneading them if necessary, and then molding them according to usual preparation techniques. The above-mentioned mixing may be a common method, for example, by mixing, kneading, or the like. Specifically, for example, when the immediate-release preparation is formed into granules, a vertical granulator (vertical granulator), a universal kneader (HATA IRON WORKS CO. , LTD), fluidized bed granulator FD-5S (POWREX CORPORATION), etc. After mixing the ingredients, wet extrusion granulation, fluidized bed granulation, etc., can be used to prepare immediate release preparations.

Immediate-release preparations and sustained-release preparations obtained in this way can be formulated into pharmaceutical preparations in the original form or together with appropriate preparation excipients by conventional methods, and then prepared in combination for administration at the same time or at regular intervals. Alternatively, the two preparations can also be made into a single oral preparation (eg granules, fine granules, tablets, capsules) in the original form or together with suitable preparation auxiliary materials. It is also possible to fill two granule or fine granule preparations into the same oral capsule.

[3] Sublingual preparations, buccal preparations or orally rapidly disintegrating preparations and their preparation

Sublingual preparations, buccal preparations or orally rapidly disintegrating preparations may be solid preparations such as tablets, or oral mucosal patch (film) (oral mucosal patch (film)).

Sublingual formulations, buccal formulations or orally rapidly disintegrating formulations are preferably formulations containing the compound of the present invention or a combination drug and excipients. The formulation may also contain auxiliary agents such as lubricants, isotonic agents, hydrophilic carriers, water-dispersible polymers, and stabilizers. In addition, in order to promote absorption and improve bioavailability, β-cyclodextrin or β-cyclodextrin derivatives (such as hydroxypropyl-β-cyclodextrin, etc.) may also be contained in the preparation.

Examples of the above excipients include lactose, saccharose, D-mannitol, starch, crystalline cellulose, light silicic anhydride and the like. Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide and the like, preferably magnesium stearate and colloidal silicon dioxide. Examples of isotonic agents include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, and urea, with mannitol being particularly preferred. As the hydrophilic carrier, for example, swelling hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linked polyvinylpyrrolidone, light silicic anhydride, silicic acid, dicalcium phosphate, calcium carbonate, etc., are preferably crystalline fibers Elements (such as microcrystalline cellulose, etc.). Examples of water-dispersible polymers include gums (such as tragacanth, gum arabic, guar gum), alginates (such as sodium alginate), cellulose derivatives (such as methylcellulose, carboxymethyl Cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, water-soluble starch, polyacrylic acid (such as carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene Glycol, polyvinylpyrrolidone, polycarbophil, ascorbyl palmitate, etc., preferably hydroxypropyl methylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, and polyethylene glycol Alcohol, especially preferably hydroxypropylmethylcellulose. As a stabilizer, cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite, etc. are mentioned, for example, Citric acid and ascorbic acid are especially preferable.

Sublingual preparations, buccal preparations or orally rapidly disintegrating preparations can be prepared by mixing the compound of the present invention or a combination drug and an excipient by a method known per se. In addition, the above-mentioned auxiliary agents, such as lubricants, isotonic agents, hydrophilic vehicles, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives, etc., may also be added if necessary. After mixing the above ingredients at the same time or at certain intervals, the compound is compressed into tablets to produce sublingual, buccal or orally rapidly disintegrating tablets. In order to obtain appropriate hardness, it may be humidified or moistened with a solvent such as water or alcohol as necessary before and after the tableting process, and then dried.

In the preparation of oral mucosal tablets (films), the compound of the present invention or the combined drug, the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), excipients, etc. Dissolving in a solvent such as water, the resulting solution is then cast to form a film. In addition, additives such as plasticizers, stabilizers, antioxidants, preservatives, colorants, buffers, sweeteners, etc. may also be added to the formulation. In order to give the film proper elasticity, glycols such as polyethylene glycol and propylene glycol can be added, and in order to improve the adhesion of the film to the oral mucosa, bioadhesive polymers (such as polycarbophile, polycarbophile, etc.) can be added. Caberbo). Casting can be performed by pouring the solution onto a non-adherent surface, spreading the solution to a uniform thickness (preferably about 10 to 1000 microns) using a doctor blade such as a doctor blade, and drying the solution to form a film. The films so formed can be dried at room temperature or under heat, after which they can be cut into small pieces with the desired surface area.

Preferred orally rapidly disintegrating agents include, for example, solid network immediate-release preparations containing the compound of the present invention or the combination drug and a water-soluble or water-insoluble carrier that is inert to the compound of the present invention or the combination drug. The network is obtained by sublimating a solvent from a solid composition comprising a solution of the compound of the present invention or a combination drug in an appropriate solvent.

In addition to the compound of the present invention or the combined drug, a matrix-forming agent and a second component may preferably be contained in the composition of the orally rapidly disintegrating agent.

Examples of matrix-forming agents include gelatin, dextrin, and animal or vegetable proteins derived from soybeans, wheat, psyllium, etc.; viscous substances such as acacia, guar, agar, xanthan, etc.; polysaccharides ; alginate; carboxymethylcellulose; carrageenan; dextran; pectin; synthetic polymers such as polyvinylpyrrolidone; Matrix forming agents also include sugars such as mannitol, glucose, lactose, galactose, trehalose and other sugars; cyclodextrin and other rings; sodium phosphate, sodium chloride, aluminum silicate and other inorganic salts; with 2 to 12 Amino acids with carbon atoms, such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, L-benzene Alanine etc.

One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification. The matrix forming agent can be present in the form added to the surfactant or in the form without the surfactant. In addition to forming a matrix, the matrix forming agent also helps to maintain the diffusion state of the compound of the present invention or combination drug in solution or suspension.

The composition may contain a second ingredient such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavours, sweeteners, taste-masking agents and the like. As a suitable coloring agent, for example, FD&C dyes such as iron oxide red, black and yellow, FD&C Blue No.2 and FD&C Red No.40 of ERIS and EVERALD companies, etc. Examples of suitable flavors include mint, cranberry, licorice, orange, lemon, grape juice, caramel, vanilla, strawberry, grape flavor, and combinations thereof. Examples of suitable pH adjusters include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Examples of suitable sweeteners include aspartame, acesulfame K and cyclamate. Examples of suitable taste-masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin-containing compounds, adsorbents, and microencapsulated apomorphine.

The preparation usually contains the compound of the present invention or the combination drug in an amount of about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight, and the preparation (the above-mentioned sublingual tablet, buccal, etc.) can make 90 % or more of the compound of the present invention or combination drug is dissolved in between about 1 to about 60 minutes, preferably between about 1 minute to about 15 minutes, more preferably between about 2 minutes to about 5 minutes ( water), or an orally rapidly disintegrating agent that disintegrates after being placed in the oral cavity in about 1 to about 60 seconds, preferably in about 1 to about 30 seconds, more preferably in about 1 to about 10 seconds.

Based on the total weight of the preparation, the content of the above-mentioned excipients is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative is about 0 to about 30% by weight relative to the total weight of the preparation. The lubricant is present in an amount of about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight, based on the total weight of the formulation. The content of the isotonic agent is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight, based on the total weight of the preparation. The content of the hydrophilic carrier is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight relative to the total weight of the preparation. The content of the water-dispersible polymer is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight relative to the total weight of the preparation. The content of the stabilizer is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight relative to the total weight of the preparation. Additives such as coloring agents, sweeteners, and preservatives may also be contained in the above-mentioned preparations as required.

The dose of the combined preparation of the present invention varies depending on the type of the compound of the present invention, age, body weight, disease, preparation form, administration route, administration period and the like.

The dose of the compound of the present invention varies according to the subject of administration, target organ, disease, route of administration, etc. During oral administration, a daily dose of about 0.1 to about 100 mg is generally given to cancer patients (body weight is recorded as 60 kg), preferably From about 1.0 to about 50 mg, more preferably from about 1.0 to about 20 mg. In the case of parenteral administration, the single dose of the compound varies depending on the administration object, target organ, disease, administration route, etc., and when it is an injection, it is preferably about 0.01 to about 30 mg per day by intravenous injection. A dosage, preferably a daily dosage of about 0.1 to about 20 mg, more preferably a daily dosage of about 0.1 to about 10 mg, is administered to a cancer patient (60 kg recorded body weight) of the compound. For other animal species, corresponding doses converted per 60 kg of body weight can be administered. Of course, the dosage varies according to the above-mentioned conditions; sometimes less than the above-mentioned dosage is sufficient, and sometimes a dosage exceeding the above-mentioned range is required.

The dose of the combination drug can be set within any range as long as it does not cause adverse reactions. The daily dose of the combination drug varies according to the degree of the disease, the age, sex, body weight and sensitivity of the subject to be administered, the cycle and interval of administration, the properties, formula, type and active ingredients of the pharmaceutical preparation, etc., and there is no special limitation. limited. For example, when administered orally, the dose of the drug is about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg; usually the dose is divided into 1 to 4 times a day.

When administering the pharmaceutical preparation of the present invention, the compound of the present invention and the combination drug can be administered simultaneously. Either the combination drug is administered first and then the compound of the present invention is administered, or the compound of the present invention is administered first and then the combination drug is administered. When the two are administered at a certain interval, the interval is different according to the active ingredient administered, the dosage form, and the route of administration; when the combination drug is administered first, it should be 1 minute to 3 days after the combination drug is administered, preferably The compounds of the invention are administered within 10 minutes to 1 day, more preferably 15 minutes to 1 hour. When the compound of the present invention is administered first, the combined drug is administered 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after the administration of the compound of the present invention.

As a preferred method of administration, for example, as a daily dose, a dose of about 0.001 to 200 mg/kg of the combination drug in the form of an oral formulation is orally administered, about 15 minutes later, a dose of about 0.005 to 0.5 mg/kg is administered parenterally Compounds of the invention in the form of parenteral formulations.

As transferins, for example, human transferins described in WO 00/24890, mouse or rat transferins described in WO 01/75104, etc. can be used.

Specific examples of human transferins include peptides consisting of 8 to 54 amino acid residues containing the N-terminal 47-54 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1.

The "peptide consisting of 8 to 54 amino acid residues containing the N-terminal 47-54 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1", as long as it contains the amino acid sequence shown in SEQ ID NO: 1 In the N-terminal 47-54 amino acid sequence, the peptide formed by 8 to 54 amino acid residues may be any peptide, but it means that these peptides have substantially the same physiological activity (for example, receptor binding activity, Signal transduction effect, effect of increasing sugar level, effect of promoting glucagon secretion, effect of promoting urine production, etc.). Specifically, the following peptides and the like are used: (i) a peptide having the amino acid sequence shown in SEQ ID NO: 1, (ii) a peptide having the N-terminal of the amino acid sequence shown in SEQ ID NO: 1 at the C-terminal 47-54 amino acid sequence, consisting of 8 to 54 amino acid residues.

More specifically, the human transferins used include the following, etc.: (i) peptides, consisting of the amino acid sequence shown in SEQ ID NO: 1 (human transferins 54 (1-54)), (ii) peptides, consisting of SEQ ID NO: 1 The N-terminal 40-54 amino acid sequence composition in the amino acid sequence shown in NO: 1 (human transferin 15 (40-54); SEQ ID NO: 15), (iii) peptide, by the amino acid sequence shown in SEQ ID NO: 1 N-terminal 45-54 amino acid sequence composition (human transferin 10 (45-54); SEQ ID NO: 16), (iv) peptide, N-terminal 46-54 in amino acid sequence shown by SEQ ID NO: 1 Amino acid sequence composition (human transferin 9 (46-54); SEQ ID NO: 17), (v) peptide, consists of the N-terminal 47-54 amino acid sequence in the amino acid sequence shown (human transferin 8 (47-54 ); SEQID NO: 18) etc.

As the mouse transferin (A), for example (i) peptide is used, which contains the N-terminal 134-141 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 3 and consists of 8 to 52 amino acid residues. More specific examples of the used mouse transferin (A) include the following etc.: (i) peptide consisting of the N-terminal 90-141 amino acid sequence of the amino acid sequence shown in SEQ ID NO: 3, (II) peptide consisting of The N-terminal 132-141 amino acid sequence of the amino acid sequence shown in SEQ ID NO:3 consists of (III) peptide, which consists of the N-terminal 127-141 amino acid sequence of the amino acid sequence shown in SEQ ID NO:3.

As the mouse transferin (B), for example, (i) peptide is used, which contains the N-terminal 138-145 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 5 and consists of 8 to 52 amino acid residues. More specific examples of the mouse transferin (B) used include (i) a peptide consisting of the N-terminal 94-145 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 5, and the like.

As the rat transferin, for example (i) peptide is used, which contains the N-terminal 112-119 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 7 and consists of 8 to 52 amino acid residues. More specific examples of rat transferins used include the following, etc.: (i) a peptide consisting of the N-terminal 68-119 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 7, (ii) a peptide consisting of SEQ ID NO: The N-terminal 110-119 amino acid sequence in the amino acid sequence shown in : 7 consists of, (iii) peptide, which consists of the N-terminal 105-119 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 7.

Transferins appearing in this specification follow the convention for describing peptides, with the N-terminus (amino-terminus) on the left-hand side and the C-terminus (carboxy-terminus) on the right-hand side. In the peptide shown in SEQ ID NO: 1, the C-terminal is any one of carboxyl (-COOH), carboxylate (-COO-), amide (-CONH ₂ ) and ester (-COOR). Specific examples of ester groups represented by R include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.; C _3-8 cycloalkyl groups such as cyclopentyl, cyclo Hexyl, etc.; C _6-12 aryl such as phenyl, α-naphthyl, etc.; C _7-14 aralkyl such as phenyl-C _1-2 alkyl, etc., such as benzyl, phenethyl, etc.; α-naphthyl-C _1-2 alkyl such as α-naphthylmethyl, etc.; pivaloyloxymethyl, which is commonly used as an ester for oral use, etc.

In addition, the transferins include the following: peptides, wherein the amino group of the N-terminal methionine residue is protected by a protecting group (for example, C _1-6 acyl such as C _2-6 alkanoyl, etc., for example, formyl, acetyl, etc. ); peptides, wherein the N-terminal part is cleaved in vivo, and the glutamyl group is thus pyroglutaminated; peptides, wherein substituents of amino acid side chains in the molecule (for example, -OH, -SH, amino, imidazole group, indolyl, guanidinyl, etc.) protected by a suitable protecting group (such as C _1-6 acyl such as C _2-6 alkanoyl, etc., such as formyl, acetyl, etc.); or complex peptides, such as with Glycopeptides bound by sugar chains.

The salt of the transferin of the present invention is preferably a salt formed with a physiologically acceptable acid (for example, an inorganic acid or an organic acid) or a base (for example, an alkali metal salt), and is particularly preferably a physiologically acceptable acid addition Salt. Examples of such salts include, for example, those formed with inorganic acids such as hydrochloric, phosphoric, hydrobromic, sulfuric; organic acids such as acetic, formic, propionic, fumaric, maleic, succinic, tartaric; , citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid), etc.

As DNAs encoding transferins, for example, DNAs encoding human transferins disclosed in WO 00/24890, DNAs encoding mouse or rat transferins disclosed in WO 01/75104, etc. are used.

The DNAs encoding transferins may be any of genomic DNA, genomic DNA library, the above-mentioned cDNA derived from cells and tissues, the above-mentioned cDNA library derived from cells and tissues, and synthetic DNA. The vector used in the library may be any of phage, plasmid, cosmid and phagemid. DNA can also be directly amplified by reverse transcription polymerase chain reaction (hereinafter abbreviated as RT-PCR) using total RNA or mRNA fractions prepared from the above cells and tissues.

As the DNA encoding human transferin, mouse transferin precursor (A), mouse transferin precursor (B) or rat transferin precursor, as long as they all contain SEQ ID NO: 2, SEQ ID NO: 4. DNA with any one of the base sequences shown in SEQ ID NO: 6 or SEQ ID NO: 8, or a DNA that can be compared with SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: Any one of the base sequences shown in 8 hybridizes under highly stringent conditions, and encodes human transferin, mouse transferin (A), mouse transferin (B) or rat transferin DNA, can be either.

As a DNA that can hybridize under highly stringent conditions with any of the base sequences shown in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8, specific examples thereof include DNAs, The DNAs contain at least about 70% homology, preferably at least at least A base sequence having about 80% homology, more preferably at least about 90% homology, especially preferably at least about 95% homology.

The homology in the base sequence can be under the following conditions (expectation value = 10; allow gap (gap); filter = ON; match score = 1; mismatch score = -3), using the homology evaluation method NCBIBLAST (National Center for Biotechnology Information Basic Local AlignmentSearch Tool) for determination.

Hybridization can be performed by the method disclosed per se or a modified method of these methods, for example, according to the method in Molecular Cloning, 2nd (J. Sambrook et al., published by Cold Spring Harbor Lab., 1989) and the like. Commercially available libraries can also be used following the specification in the accompanying manufacturer's protocol. It is preferred to perform hybridization under highly stringent conditions.

Highly stringent conditions used here are, for example, a sodium concentration of about 19 to 40 mM, preferably about 19 to 20 mM, and a temperature of about 50 to 70°C, preferably about 60 to 65°C. It is especially preferred to carry out the hybridization at a sodium concentration of about 19 mM and a temperature of about 65°C.

Specifically, as the DNA encoding human transferin consisting of the amino acid sequence represented by SEQ ID NO: 1, a DNA consisting of the base sequence represented by SEQ ID NO: 2 was used. Therefore, for the base sequence encoding the human transferin composed of the above-mentioned different amino acid sequences, each part of the amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1 can be selected from the base sequence shown in SEQ ID NO: 2 corresponding base sequence.

As the DNA encoding the mouse transferin precursor (A) comprising the amino acid sequence shown in SEQ ID NO: 3, DNA consisting of the base sequence shown in SEQ ID NO: 4 or the like is used. Therefore, for the base sequence of the mouse transferin precursor (A) that is composed of the above-mentioned different amino acid sequences, it can be selected from the base sequence shown in SEQ ID NO: 4 and the amino acid sequence shown in SEQ ID NO: 3 The base sequence corresponding to each part of the amino acid sequence.

As the DNA encoding the mouse transferin precursor (B) comprising the amino acid sequence shown in SEQ ID NO: 5, DNA consisting of the base sequence shown in SEQ ID NO: 6 or the like is used. Therefore, for the base sequence of the mouse transferin precursor (B) that is composed of the above-mentioned different amino acid sequences, it can be selected from the base sequence shown in SEQ ID NO: 6 and the amino acid sequence shown in SEQ ID NO: 5 The base sequence corresponding to each part of the amino acid sequence.

As the DNA encoding the rat transferin comprising the amino acid sequence shown in SEQ ID NO: 7, a DNA consisting of the base sequence shown in SEQ ID NO: 8 or the like is used. Therefore, for the base sequence encoding the rat transferin composed of the above-mentioned different amino acid sequences, each part of the amino acid in the amino acid sequence shown in SEQ ID NO: 7 can be selected from the base sequence shown in SEQ ID NO: 8 The base sequence corresponding to the sequence.

More specifically, for a peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 (human transferin 54(1-54)), DNA containing the base sequence shown in SEQ ID NO: 2 or the like is used.

For the peptide (human transferin 15 (40-54); SEQ ID NO: 15) consisting of the N-terminal 40-54 amino acid sequence of the amino acid sequence shown in SEQ ID NO: 1, use a base containing the base shown in SEQ ID NO: 19 base sequence DNA, etc.

For the peptide (human transferin 10 (45-54); shown in SEQ ID NO: 16) composed of the N-terminal 45-54 amino acid sequence of the amino acid sequence shown in SEQ ID NO: 1, use the peptide containing SEQ ID NO: 20 DNA showing the base sequence, etc.

For the peptide (human transferin 9 (46-54); shown in SEQ ID NO: 17) composed of the N-terminal 46-54 amino acid sequence of the amino acid sequence shown in SEQ ID NO: 1, use the peptide containing SEQ ID NO: 21 DNA showing the base sequence, etc.

For the peptide (human transferin 8 (47-54); shown in SEQ ID NO: 18) composed of the N-terminal 47-54 amino acid sequence of the amino acid sequence shown in SEQ ID NO: 1, use the peptide containing SEQ ID NO: 22 DNA showing the base sequence, etc.

As transferin receptors, peptide fragments thereof, or salts thereof, for example, human transferin receptors disclosed in WO 00/24890, peptide fragments thereof, or salts thereof, the mouse receptors disclosed in WO 01/75104, Or rat human transferin receptor, its peptide fragments or their salts, etc.

Specifically, the transferin receptors include proteins containing amino acid sequences identical or substantially identical to those shown in SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13.

Amino acid sequences substantially identical to the amino acid sequence set forth in SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 include, for example, amino acid sequences identical to SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 The amino acid sequences shown have at least about 70% homology, preferably at least about 80% homology, more preferably at least about 90% homology, most preferably at least about 95% homology amino acid sequences.

The homology of amino acid sequences can be determined using the homology evaluation method NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) under the following conditions (expectation value = 10; gaps allowed; matrix = BLOSUM62; filter = OFF).

As a protein having an amino acid sequence substantially identical to the amino acid sequence shown in SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, preferably having the same amino acid sequence as SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 11 or SEQ ID NO: An amino acid sequence substantially identical to the amino acid sequence shown in ID NO: 13, and a protein having substantially the same properties and activities as a protein consisting of the amino acid sequence shown in SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 wait.

"Activities of substantially the same nature" include, for example, ligand-binding activity, signal transduction activity, and the like. "Essentially the same properties" means that the properties of their activities are comparable. Therefore activities such as ligand binding activity, signal transduction activity, etc. are preferably comparable (for example, about 0.01 to 100 times, preferably about 0.1 to 10 times, more preferably 0.5 to 2 times), but the degree of their activity level , Quantitative factors such as molecular weight of protein etc. can also be different.

Activities such as ligand binding activity, signal transduction activity, etc. can be determined by modifications of methods known per se, for example, they can be determined according to the ligand determination and screening methods disclosed in WO 00/24890 or WO 01/75104.

As a transferin receptor, a protein comprising the following amino acid sequence can be used: (1) (i) the amino acid sequence shown in SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, wherein at least 1 or 2 ( Preferably from about 1 to about 30, more preferably from about 1 to about 10, most preferably several (1 or 2)) amino acids; (ii) SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 The amino acid sequence shown, wherein at least 1 or 2 (preferably about 1 to about 30, more preferably about 1 to about 10, most preferably several (1 or 2)) amino acids have been added; (iii) SEQ ID NO: 9. The amino acid sequence shown in SEQ ID NO: 11 or SEQ ID NO: 13, wherein at least 1 or 2 (preferably about 1 to about 30, more preferably about 1 to about 10, most preferably several (1 or 2 )) amino acids; (iv) the amino acid sequence shown in EQIDNO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, wherein at least 1 or 2 (preferably about 1 to about 30, more preferably about 1 to about 10 , most preferably several (1 or 2) amino acids are substituted by other amino acids; or (v) a combination of the above amino acid sequences; and so on.

The transferin receptors in this specification are indicated following the convention for describing peptides, ie, the N-terminus (amino-terminus) is on the left-hand side and the C-terminus (carboxyl-terminus) is on the right-hand side. In the transferin receptors including those shown by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, the C-terminus can be carboxyl (-COOH), carboxylate (-COO Any form of -), amide (-CONH ₂ ) and ester (-COOR). Specific examples of ester groups represented by R include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.; C _3-8 cycloalkyl groups such as cyclopentyl, cyclo Hexyl, etc.; C _6-12 aryl such as phenyl, α-naphthyl, etc.; C _7-14 aralkyl such as phenyl-C _1-2 alkyl, etc., such as benzyl, phenethyl, etc.; α-naphthyl-C _1-2 alkyl such as α-naphthylmethyl, etc.; pivaloyloxymethyl, which is commonly used as an ester for oral use, etc.

When the transferin receptor has a carboxyl group (or carboxylate) at a position other than the C-terminus, and the carboxyl group is amidated or esterified, then the amide or ester is also included in the receptor protein of the present invention . In this case, as the ester group, the same ones as the above-mentioned C-terminal ester can be used.

In addition, the transferin receptors include the following: wherein the amino group of the N-terminal methionine residue is protected by a protecting group (for example, C _1-6 acyl such as C _2-6 alkanoyl, etc., for example, formyl, acetyl, etc. ); those in which the N-terminal portion is cleaved in vivo so that the glutamyl group formed is pyroglutaminated; Amino, imidazolyl, indolyl, guanidinyl, etc.) are protected by suitable protecting groups (such as C _1-6 acyl such as C _2-6 alkanoyl, etc., such as formyl, acetyl, etc.) protected; or Conjugated proteins, such as glycoproteins bound to sugar chains.

Specific examples of transferin receptors include: a human transferin receptor consisting of the amino acid sequence shown in SEQ ID NO: 9, a rat transferin receptor consisting of the amino acid sequence shown in SEQ ID NO: 11, a transferin receptor consisting of the amino acid sequence shown in SEQ ID NO : The mouse transferin receptor composed of the amino acid sequence shown in 13, etc.

As long as the peptide fragment of the transferin receptor (hereinafter, sometimes referred to simply as the peptide fragment) is the above-mentioned peptide fragment of the transferin receptor, it may be any peptide; A peptide fragment that is located outside the cell membrane and has ligand-binding activity.

Specifically, a peptide fragment that is a transferin receptor consisting of the amino acid sequence shown in SEQ ID NO: 9, SEQ ID NO: 11, or SEQ ID NO: 13, is a peptide fragment identified in hydrophobic plotting analysis as Peptides that are part of the extracellular domain (hydrophilic domain). Peptides partially containing hydrophobic domains can also be used. In addition, the peptide may contain individual domains or may contain a plurality of domains at the same time.

In the transferin receptor, a preferred peptide fragment is a peptide having at least 20 amino acids, preferably at least 50 amino acids, and especially preferably at least 100 amino acids in the above amino acid sequence constituting the transferin receptor.

The peptide fragment may be a peptide having the above amino acid sequence, wherein at least 1 or 2 (preferably about 1 to about 10, more preferably several (1 or 2)) amino acids are deleted; wherein at least 1 or 2 (preferably About 1 to about 10, more preferably several (1 or 2)) amino acids; or wherein at least 1 or 2 (preferably about 1 to about 10, more preferably several (1 or 2)) amino acids are substituted by other amino acids .

In the peptide fragment, as with the above-mentioned transferin receptor, the C-terminus may be in any form of carboxyl group (-COOH), carboxylate (-COO-), amide (-CONH ₂ ) and ester (-COOR).

In addition, the same as the above-mentioned transferin receptors, peptide fragments include the following: peptides in which the amino group of the N-terminal methionine residue is protected by a protecting group; Those that are glutamylated; those in which the substituents of the side chains of amino acids in the molecule are protected with appropriate protecting groups; or conjugated peptides such as glycopeptides bonded to sugar chains.

For the salts of transferin receptors or peptide fragments, salts with physiologically acceptable acids are preferred, and physiologically acceptable acid addition salts are particularly preferred. Examples of such salts include, for example, those formed with inorganic acids such as hydrochloric, phosphoric, hydrobromic, sulfuric; organic acids such as acetic, formic, propionic, fumaric, maleic, succinic, tartaric; , citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid), etc.

As DNA encoding a transferin receptor or a peptide fragment thereof, for example, the DNA encoding a human transferin receptor or a peptide fragment thereof disclosed in WO 00/24890, the DNA encoding a mouse or rat peptide disclosed in WO 01/75104 , DNA of human transferin receptor and its peptide fragment, etc.

DNAs encoding transferin receptors or peptide fragments thereof may be any of genomic DNA, genomic DNA library, the above-mentioned cDNA from cells and tissues, the above-mentioned cDNA library from cells and tissues, and synthetic DNA. The vector used in the library may be any of phage, plasmid, cosmid and phagemid. DNA can also be directly amplified by reverse transcription polymerase chain reaction (hereinafter abbreviated as RT-PCR) using total RNA or mRNA fractions prepared from the above cells and tissues.

Specifically, as the DNA encoding human transferin receptor, mouse transferin receptor or rat transferin receptor, as long as the DNA contains SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14 The DNA of each base sequence shown, or the DNA contains a base sequence that can hybridize with the base sequence shown in SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14 under highly stringent conditions, and encodes The receptor is substantially identical to the human transferin receptor, mouse transferin receptor or rat transferin receptor consisting of the amino acid sequence shown in SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14 properties (eg, ligand binding activity, signal transduction activity, etc.).

As the DNA that hybridizes to the base sequence shown in any one of SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14, specific examples thereof include DNAs containing , the base sequence shown in any one of SEQ ID NO: 12 or SEQ ID NO: 14 has at least about 70% homology, preferably at least 80% homology, more preferably at least 90% homology, Base sequences with at least 95% homology are most preferred.

The homology in the base sequence can be under the following conditions (expectation value=10; allow gap; filter=ON; match score=1; mismatch score=-3), using the homology evaluation method NCBIBLAST (National Center for Biotechnology Information Basic Local AlignmentSearch Tool) for determination.

Hybridization can be performed by the method disclosed per se or a modified method of these methods, for example, according to the method in Molecular Cloning, 2nd (J. Sambrook et al., published by Cold Spring Harbor Lab., 1989) and the like. Commercially available libraries can also be used following the specification in the accompanying manufacturer's protocol. It is preferred to perform hybridization under highly stringent conditions.

Highly stringent conditions used here are, for example, a sodium concentration of about 19 to 40 mM, preferably about 19 to 20 mM, and a temperature of about 50 to 70°C, preferably about 60 to 65°C. Most preferably, the hybridization is performed at a sodium concentration of about 19 mM and a temperature of about 65°C.

More specifically, as the DNA encoding the human transferin receptor consisting of the amino acid sequence shown in SEQ ID NO: 9, a DNA consisting of the base sequence of SEQ ID NO: 10 was used.

As the DNA encoding the rat transferin receptor consisting of the amino acid sequence shown in SEQ ID NO: 11, the DNA consisting of the base sequence shown in SEQ ID NO: 12 was used.

As the DNA encoding the mouse transferin receptor consisting of the amino acid sequence shown in SEQ ID NO: 13, the DNA consisting of the base sequence shown in SEQ ID NO: 14 was used.

Transferin receptors, peptide fragments thereof or salts thereof, and DNAs encoding transferin receptors or peptide fragments thereof can be obtained by the methods disclosed in WO 00/24890 or WO 01/75104.

Hereinafter, the present invention will be described in more detail in Examples, Formulation Examples and Test Examples, but these are not limiting, and arbitrary changes can be made within the scope of the present invention.

In the following examples, "room temperature" generally refers to a temperature of about 10°C to 35°C. For percentages, yields are expressed in mol/mol%, solvents used in chromatography are expressed in vol%, and otherwise are expressed in wt%. In proton NMR spectra, OH, NH protons, etc. are broad and cannot be identified and are not shown in the data.

The meanings of other abbreviations used in the specification are as follows.

acronym meaning

10Ψ, CSNH: 10-position C-terminal -CONH2 is replaced by -CSNH ₂

1Ψ2, CH ₂ NH: The -CONH- bond between the 1- and 2-positions is replaced by a -CH ₂ NH- bond

2Ψ3, CH ₂ NH: The -CONH- bond between the 2- and 3-positions is replaced by a -CH ₂ NH- bond

3Ψ4, CH ₂ NH: The -CONH- bond between the 3- and 4-positions is replaced by a -CH ₂ NH- bond

4Ψ5, CH ₂ NH: The -CONH- bond between the 4- and 5-positions is replaced by a -CH ₂ NH- bond

6Ψ7, CSNH: The -CONH- bond between the 6- and 7-positions is replaced by a -CSNH- bond

6Ψ7, NHCO: The -CONH-bond between the 6- and 7-positions is replaced by a -NHCO-bond

6Ψ7, CH ₂ NH: The -CONH- bond between the 6- and 7-positions is replaced by a -CH ₂ NH- bond

6Ψ7, CH ₂ O: The -CONH- bond between the 6- and 7-positions is replaced by a -CH ₂ O- bond

7Ψ8, CH ₂ NH: The -CONH- bond between the 7- and 8-positions is replaced by a -CH ₂ NH- bond

8Ψ9, CH ₂ NH: The -CONH- bond between the 8- and 9-positions is replaced by a -CH ₂ NH- bond

9Ψ10, CH ₂ NH: The -CONH- bond between the 9- and 10-positions is replaced by a -CH ₂ NH- bond

Abu: 2-aminobutyric acid

Ac: Acetyl

Acp: 6-aminocaproic acid

AcOEt: ethyl acetate

AcOH: acetic acid

Aib: α-aminoisobutyric acid

Ala(2-Qui): 2-quinolylalanine

Ala(3-Bzt): 3-Benzothienylalanine

Alb: Albisine 2-amino-3-ureidopropionic acid

Arg(Ac): N ^ω -acetyl arginine

Arg(Boc ₂ , Me): N ^ω,ω′ -di-tert-butoxycarbonyl-N ^ω -methylarginine

Arg(Et): N ^ω -Ethyl Arginine

Arg(Me): N ^ω -methylarginine

Arg(asyMe ₂ ) or Arg(Me ₂ )asym: asymmetric-N ^ω,ω -dimethylarginine

Arg(symMe ₂ ) or Arg(Me ₂ )sym: symmetric-N ^ω,ω′ -dimethylarginine

Arg(NO ₂ ): N ^ω -methylarginine

Arg(n-Pr): N ^ω -Propyl arginine

Arg(Tos): N ^ω -Tosyl Arginine

Asp(NHMe): N ^ω -methylasparagine

Asp(Nme2): N ^ω -dimethylasparagine

AzaGly: Azaglycine

AzaPhe: Azaphenylalanine

Aze(2): Azetidine-2-carboxylic acid

β-Ala: β-alanine

Boc: tert-butoxycarbonyl

Boc ₂ O: Di-tert-butyl dicarbonate

Br-Z : 2-bromobenzyloxycarbonyl

^But : tert-butyl

Bzl: benzyl

CDI: 1,1'-carbonyldiimidazole

Cha: Cyclohexylalanine

CIP: 2-chloro-1,3-dimethylimidazolium tetrafluoroborate

Cit: Citrulline

Clt resin: 2-chlorotrityl resin

Cl-Z: 2-chlorobenzyloxycarbonyl

Dab: 2,4-diaminobutyric acid

Dap: 2,3-Diaminopropionic acid

Dap(Ac): N ^β -acetyl diaminopropionic acid

Dap(For): N ^β -formyl diaminopropionic acid

Dap(Gly): N ^β -glycyl diaminopropionic acid

Dap(GnGly): N ^β -(N-guanidinoglycyl) diaminopropionic acid

DCM: dichloromethane

DEA: Diethylamine

DIEA: N,N-Diisopropylethylamine

DIPCDI: 1,3-Diisopropylcarbodiimide

DMAP: 4-Dimethylaminopyridine

DMF: N,N-Dimethylformamide

EDT: 1,2-ethanedithiol

Fmoc: 9-fluorenylmethoxycarbonyl

For: Formyl

γ-Abu: 4-aminobutyric acid

γ-MeLeu: γ-methylleucine

Gn: guanidino

GuAmb: 4-guanidinomethylbenzoyl

Har: high arginine

Har(Me): N ^ω -Methylhomoarginine

HOAt: 1-Hydroxy-7-azabenzotriazole

HOBt: 1-Hydroxybenzotriazole

HONB: N-Hydroxy-5-norbornene-2,3-dicarboxamide

Hph: Homophenylalanine

Hyp: trans-4-hydroxyproline

IndPr: 3-(indol-3-yl)propionyl

Lys(Me ₂ ): N ^ε,ε -Dimethyllysine

MBHA: p-Methylbenzhydrylamine

MeOH: Methanol

Mtt: 4-Methyltrityl

N((CH ₂ ) ₃ Gn)Gly: N-(3-guanidinopropyl)glycine

Nal(1): 1-Naphthylalanine

Nal(2): 2-Naphthylalanine

Nar: norarginine

Nar(Me): N ^{ω -methyl} -nor-arginine

Nle: norleucine

NMeArg: N ^α -methylarginine

NMeAsn: N ^α -methylasparagine

NMeLeu: N ^α -methylleucine

NMePhe: N ^α -methylphenylalanine

NMeSer: N ^α -methylserine

NMeTrp: N ^α -methyl tryptophan

NMeTyr: N ^α -methyltyrosine

Nva: Norvaline

Orn: ornithine

Orn(Mtt): N ^δ -(4-methyltrityl)ornithine

PAL: 5-(4-(9-fluorenylmethoxycarbonyl)aminomethyl 3,5-dimethoxyphenoxy)pentanoic acid

Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

pGlu: pyroglutamic acid

Phe(2Cl): 2-chlorophenylalanine

Phe(2F): 2-fluorophenylalanine

Phe(3,4Cl ₂ ): 3,4-dichlorophenylalanine

Phe(3,4F ₂ ): 3,4-difluorophenylalanine

Phe(3CF ₃ ): 3-trifluoromethylphenylalanine

Phe(3Cl): 3-chlorophenylalanine

Phe(3F): 3-fluorophenylalanine

Phe(4Cl): 4-chlorophenylalanine

Phe(4CN): 4-cyanophenylalanine

Phe(4F): 4-fluorophenylalanine

Phe(4Gn): 4-guanidinophenylalanine

Phe(4NH ₂ ): 4-aminophenylalanine

Phe(4NO ₂ ): 4-nitrophenylalanine

Phe(4CN): 4-cyanophenylalanine

Phe(F ₅ ): Pentafluorophenylalanine

PheΨ(CH ₂ O)Gly: The -CONH- bond between Phe and Gly is replaced by a -CH ₂ O- bond

PheΨ(CSNH)-NH ₂ : C-terminal phenylalanylamide is replaced by phenylalanylthioamide.

Phg: Phenylglycine

PhOH: phenol

PhSMe: Thioanisole

Pip(2): 2-aminopipecolinic acid (2-aminopipecolinic acid)

Pro: Proline

Pya(2): 2-pyridylalanine

Pya(3): 3-pyridylalanine

Pya(4): 4-pyridylalanine

PyAOP: (7-Azabenzotriazol-1-yloxy)-tris(pyrrolidinyl)phosphonium hexafluorophosphate

PyBOP: (Benzotriazol-1-yloxy)-tris(pyrrolidinyl)phosphonium hexafluorophosphate

PyBrop: bromo-tris(pyrrolidinyl)phosphonium hexafluorophosphate

Sar: N-methylglycine

Ser(Ac): O-acetylserine

Ser(Me): O-methylserine

Thi: 2-thienylalanine

Tic: 1,2,3,4-tetrahydroisoquinoline-2-caarboxylic acid

TIS: Triisopropylsilane

Tle: tert-leucine

Tos: Tosyl

Trp(For): N ⁱⁿ -formyl tryptophan

Trt: Trityl

Tyr(Me): O-methyltyrosine

TyrΨ(CH ₂ NH)Asn: the -CONH- bond between Tyr and Asn is replaced by a -CH ₂ NH- bond

TFA: Trifluoroacetic acid

TFE: Trifluoroethanol

Z: Benzyloxycarbonyl

In the specification and drawings, the codes of bases and amino acids are used in accordance with IUPAC-IUB Commission on Biochemical Nomenclature (Biochemical Nomenclature Committee) or customary codes in the technical field, as shown below. For amino acids with optical isomers, unless otherwise specified, they refer to the L-form.

DNA: deoxyribonucleotides

cDNA: complementary deoxyribonucleic acid

A: adenine

T: Thymine

G: Guanine

C: Cytosine

Y: thymine or cytosine

N: thymine, cytosine, adenine or guanine

R: adenine or guanine

M: cytosine or adenine

W: thymine or adenine

S: cytosine or guanine

RNA: ribonucleic acid

mRNA: messenger ribonucleic acid

dATP: deoxyadenosine triphosphate

dTTP: deoxythymidine triphosphate

dGTP: deoxyguanosine triphosphate

dCTP: deoxycytidine triphosphate

ATP: Adenosine triphosphate

EDTA: ethylenediaminetetraacetic acid

SDS: Sodium Dodecyl Sulfate

TFA: Trifluoroacetic acid

EIA: enzyme immunoassay

Gly or G: Glycine

Ala or A: Alanine

Val or V: Valine

Leu or L: Leucine

Ile or I: Isoleucine

Ser or S: Serine

Thr or T: threonine

Cys or C: cysteine

Met or M: Methionine

Glu or E: glutamic acid

Asp or D: aspartic acid

Lys or K: Lysine

Arg or R: Arginine

His or H: Histidine

Phe or F: Phenylalanine

Tyr or Y: Tyrosine

Trp or W: Tryptophan

Pro or P: Proline

Asn or N: Asparagine

Gln or Q: Glutamine

pGlu: pyroglutamic acid

The sequence numbers in the sequence listing in the specification represent the following sequences, respectively.

SEQ ID NO: 1

The amino acid sequence of human transferin (transferin) is shown.

SEQ ID NO: 2

Base sequence of DNA encoding human transferin.

SEQ ID NO: 3

Amino acid sequence of mouse transferin precursor (A).

SEQ ID NO: 4

The nucleotide sequence of the DNA encoding the mouse transferin precursor (A) contained in the plasmid pCMV-mKiSS-1 carried by the transformant Escherichia coli (Escherichia coli) DH10B/pCMV-mKiSS-1 is shown .

SEQ ID NO: 5

The amino acid sequence of mouse transferin precursor (B) is shown.

SEQ ID NO: 6

Shown is the nucleotide sequence of the DNA encoding the mouse transferin precursor (B), which is contained in the plasmid pCR2.1-mKiSS- 1.4A.

SEQ ID NO: 7

The rat-derived transferin precursor amino acid sequence is shown.

SEQ ID NO: 8

The DNA base sequence encoding the rat transferin precursor is shown.

SEQ ID NO: 9

The amino acid sequence of human OT7T175 (transferin receptor) is shown.

SEQ ID NO: 10

The base sequence of DNA encoding human OT7T175 (transferin receptor) is shown.

SEQ ID NO: 11

The amino acid sequence of rat OT7T175 (transferin receptor) is shown.

SEQ ID NO: 12

The base sequence of DNA encoding rat OT7T175 (transferin receptor) is shown.

SEQ ID NO: 13

The amino acid sequence of mouse OT7T175 (transferin receptor) is shown.

SEQ ID NO: 14

The base sequence of DNA encoding mouse OT7T175 (transferin receptor) is shown.

SEQ ID NO: 15

The amino acid sequence of human transferin 15(40-54) is shown.

SEQ ID NO: 16

The amino acid sequence of human transferin 10(45-54) (MS10) is shown.

SEQ ID NO: 17

The amino acid sequence of human transferin 9 (46-54) is shown.

SEQ ID NO: 18

The amino acid sequence of human transferin 8 (47-54) is shown.

SEQ ID NO: 19

The base sequence of DNA encoding human transferin 15(40-54) is shown.

SEQ ID NO: 20

The base sequence of DNA encoding human transferin 10(45-54) is shown.

SEQ ID NO: 21

The base sequence of DNA encoding human transferin 9(46-54) is shown.

SEQ ID NO: 22

The base sequence of the DNA encoding human transferin 8 (47-54) is shown

The transformant Escherichia coli DH10B/pCMV-mKiSS-1 was deposited on January 24, 2000 at Industrial Technology General Corporation, an independent administrative corporation located in Japan, Tsukuba City, Ibaraki Prefecture, Higashi 1-chome 1 Banji 1 Central No. 6 (postal code 305-8566) Institute of Patent Organisms Deposit Center (former Ministry of International Trade and Industry Institute of Life Industry Technology Institute of Industrial Technology) (International Patent Organisms Depository, National Institute of Advanced Industrial Science and Technology (the former Ministry of International Trade and Industry, Agency of Industrial Science and Technology, National Institute of Bioscience andhuman Technology (NIBH)), located at central 6, 1-1-1 Higashi, Tsukuba, Ibaraki (postal code 305-8566), Japan), deposit number is FERM BP-7003; on December 16, 1999 Preserved at the Institute for Fermentation (IFO), located at 2-17-85 Juso-Honmachi, Yodogawa-ku, Osaka-shi, Osaka, Japan, located at 2-17-85, Yodogawa District, Osaka City, Osaka Prefecture, Japan. Japan), the deposit number is IFO16348.

The transformant Escherichia coli DH5α/pCR2.1-mKiSS-1.4A was deposited on March 6, 2000 at an independent institution located at No. 1 Central 6 (postal code 305-8566), Tsukuba City, Ibaraki Prefecture, Japan. Administrative legal entity Industrial Technology Research Institute Patent Organisms Deposit Center (formerly Ministry of International Trade and Industry Industrial Technology Research Institute of Life Industry Technology), the deposit number is FERM BP-7073; it was deposited in Yodogawa, Osaka City, Osaka Prefecture, Japan on February 16, 2000 Fermentation Research Institute, 2-17-85, Jusan Honcho, Ward, Accession No. IFO16360.

In the present invention, Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂ (SEQ ID NO: 16) is recorded as transferin 10 (transferin 10), namely MS10.

In the examples described later, the N-terminal Tyr and C-terminal Phe in MS10 are recorded as positions 1 and 10, respectively.

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

1 2 3 3 4 5 6 7 8 9 10

For example, [Hph10]MS10 of Compound No. 79 (Example 1) represents a peptide in which C-terminal Phe (10-position) in MS10 is substituted by Hph.

For example, des(1)-MS10 of Compound No. 4 represents a peptide in which N-terminal Tyr (1-position) is deleted.

For example, des(1-3)-Fmoc-MS10 of Compound No. 53 represents a peptide in which the N-terminal Tyr-Asn-Trp (1 to 3-position) is deleted, and the amino group of the 4-position Asn is modified and replaced by Fmoc protection.

[Example 1]

(Synthetic Method A): Preparation of [Hph10]MS10 (Compound No. 79)

Use Fmoc-Hph-PAL resin 51mg (sub.0.39mmol/g), this resin obtains by introducing Fmoc-Hph into commercially available PAL resin, utilizes multifunctional polypeptide synthesizer ACT-396 to extend the peptide chain, obtains Tyr( ^But ) Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheGlyLeuArg(Pbf)Hph-PAL resin. To 18.2 mg of this resin, 200 μL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added, and the mixture was shaken for 2 hours. Diethyl ether was then added to the reaction solution, the obtained precipitate was centrifuged, and the supernatant was removed. This process is repeated several times for cleaning. The residue was extracted with aqueous acetic acid solution, and the extract was filtered to remove the resin. Afterwards, using preparative HPLC utilizing a YMCD-ODS-5-ST S-5 120A column (20×150 mm), an eluent in the ratio of eluent A/B: 73/27-63/37: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA for linear concentration gradient elution. Fractions containing the product were pooled and lyophilized to give 2.6 mg of a white powder.

Mass spectrum (M+H) ⁺ 1316.5 (calculated 1316.7)

HPLC elution time: 20.6min

Elution condition

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: a linear concentration gradient elution of eluent A/B=100/0-30/70 was used, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins. )

Flow rate: 1.0ml/min.

[Example 2]

(Synthetic Method B): Preparation of [Trp(For)10]MS10 (Compound No. 186)

379 mg of Fmoc-Arg(Pbf)-O-Clt resin (sub.0.33 mmol/g) was used by introducing Fmoc-Arg(Pbf)-OH to commercially available 2-chlorotrityl chloride resin (Clt resin, 1.33mmol/g), and the peptide chain was extended on ABI433A to obtain 540mg of Boc-Tyr(But)Asn( ^Trt )Trp(Boc)Asn(Trt)Ser( ^But )PheGlyLeuArg(Pbf) -O-Clt resin. To 270 mg of the peptide was added 10 mL of AcOH/TFE/DCM (1/1/8), and the mixture was shaken for 30 minutes. Afterwards the resin was removed by filtration, the solvent was concentrated and the residue was dissolved in AcOEt. The solution was then washed with saturated aqueous NaCl. After drying with _{Na2SO4 ,} the solvent was concentrated, ether-petroleum ether was added to the residue to obtain 68 mg as Boc-Tyr( ^But )Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheGlyLeuArg( Precipitate of Pbf)-OH. To 22 mg of peptide was added 4 mg of HCl H-Trp(For) _-NH2 (prepared by treating Boc-Trp(For) _-NH2 with 9.7N HCl/dioxane at 0°C for 30 minutes), 10 mg of PyAOP, 5 mg of HOAt and 11 μL of DIEA. The mixture was stirred for 15 hours. After the solvent was concentrated, chloroform-diethyl ether was added to the residue to give Boc-Tyr( ^But )Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheGlyLeuArg(Pbf)Trp(For) _-NH2 of sediment. To the peptide was added 1 mL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5), and the mixture was stirred for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged, and the supernatant was removed. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution, and the extract was filtered to remove the resin. Afterwards, using preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20×150mm), using eluent A according to the ratio of eluent A/B: 73/27-63/37: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA for linear concentration gradient elution (30 minutes). Fractions containing the product were pooled and lyophilized to give 2.0 mg of a white powder.

Mass spectrum (M+H) ⁺ 1369.3 (calculated 1369.6)

HPLC elution time: 19.6min

Elution condition

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

[Example 3]

(Synthetic Method C): Preparation of [10Ψ, CSNH]MS10 (Compound No. 128)

After 264 mg of Boc-Phe-NH ₂ was dissolved in 20 mL of THF, 1.62 g of Lawesson's reagent was added to the solution, followed by stirring for 24 hours. Insoluble materials were removed by filtration, the solvent was concentrated, and the concentrate was dissolved in AcOEt. The solution was washed first with saturated aqueous NaHCO ₃ and then with saturated aqueous NaCl. After drying over _Na2SO4 , the solvent was concentrated and the concentrate was purified _by flush column chromatography. Diethyl ether-petroleum ether was then added to obtain 275 mg (98% yield) as (S)-2-tert-butoxycarbonylamino-3-phenylpropylthioamide (Boc-PheΨ(CSNH)-NH ₂ ) of sediment. After 42mg of the peptide was treated with 9.7N HCl at 0°C to remove Boc, it was treated with 10% DEA/DMF to remove Fmoc, and then concentrated using the PyBOP/HOBt method. This process was repeated several times to obtain 66mg of Fmoc-LeuArg ( Pbf)PheΨ(CSNH)-NH ₂ (yield 93%). Add H-LeuArg( ^Pbf )PheΨ(CSNH)-NH to 17mg of Boc-Tyr(But)Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheGly-OH prepared as in Example 2 ₂ (prepared by treating 14 mg of Fmoc-LeuArg(Pbf)PheΨ(CSNH) _-NH2 with 10% DEA/DMF), 9 mg of PyBrop, 3 mg of HOAt and 7 mL of DIEA, and the mixture was stirred for 15 hours. After the solvent was concentrated, chloroform-diethyl ether was added thereto to obtain a precipitate. To 10 mg of the product therein was added 100 μL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5), and the mixture was stirred for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged, and the supernatant was removed. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution, and the extract was filtered to remove the resin. Afterwards, using preparative HPLC utilizing a YMCD-ODS-5-ST S-5 120A column (20×150 mm), an eluent according to the ratio of eluent A/B: 72/28-62/38: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (30 minutes). Fractions containing the product were pooled and lyophilized to give 1.0 mg of a white powder.

Mass spectrum (M+H) ⁺ 1318.4 (calculated 1318.6)

HPLC elution time: 21.8min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: a linear concentration gradient elution of eluent A/B=100/0-30/70 was used, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.) .

Flow rate: 1.0ml/min

[Example 4]

(Synthetic Method D): Preparation of [6Ψ7, CH ₂ NH]MS10 (Compound No. 163)

Using 321 mg of Fmoc-Phe-PAL resin obtained by introducing Fmoc-Phe into commercially available PAL resin, the peptide chain was extended on ABI433A to obtain Fmoc-LeuArg(Pbf)Phe-PAL resin. For half the volume of this peptide, Fmoc-Gly was concentrated to give 190 mg of Fmoc-GlyLeuArg(Pbf)Phe-PAL resin. After 76 mg of the product was de-Fmoc-protected, 2 mL of DMF, 50 μL of AcOH, 46 mg of Fmoc-Phe-H, and 8 mg of NaBH ₃ CN were added thereto and shaken for another 1 hour. After the resin was washed, 2 mL of DMF, 22 μL of DIEA, and 18 μL of Z-Cl were further added thereto, and the mixture was shaken for 3 hours. After washing the resin, use ABI433A to extend the peptide chain to obtain Boc-Tyr(But )Asn( ^Trt )Trp(Boc)Asn(Trt)Ser( ^But )PheΨ(CH ₂ NZ)GlyLeuArg(Pbf)Phe-PAL resin . Under ice-cooling, 46 µL of TMS-Br, 42 µL of PhSMe, 38 µL of m-cresol, 18 µL of EDT, and 227 µL of TFA were added to 15 mg of the peptide, and the mixture was stirred for 2 hours. The solvent was distilled off, diethyl ether was added to the residue, the resulting precipitate was centrifuged and the supernatant was removed. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution, and the extract was filtered to remove the resin. Afterwards, using preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20×150 mm), the eluent according to the ratio of eluent A/B: 72/28-62/38: 0.1 %TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (30 minutes). Fractions containing the product were pooled and lyophilized to give 2.0 mg of a white powder.

Mass spectrum (M+H) ⁺ 1288.7 (calculated 1288.7)

HPLC elution time: 18.2min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-0/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

(Reference Example 1)

Preparation of N-methyl-N, N'-di-Boc-1-amidinopyrazole

Under nitrogen flow, dissolve 720 mg of 60% NaH oil solution in 20 mL of anhydrous DMF, and add 5.59 g of commercially available N,N′-di-Boc-1-amidinopyrazole in anhydrous DMF solution of 20 mL at 0°C , and then stirred for 10 minutes. Thereafter, 1.68 mL of methyl iodide was added thereto, and the mixture was stirred at room temperature for 24 hours. After evaporation of the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flushing column chromatography (ethyl acetate/n-hexane=1/4) using silica gel 60 (200 mL) to obtain 5.35 g (yield 91.6%) N-Methyl-N,N'-di-Boc-1-amidinopyrazole.

¹ H NMR (300MHz, CDCl ₃ ): δ8.00(br s, 1H), 7.69(br s, 1H), 6.42(dd 1H, J=2.7, 1.5Hz), 3.25(s, 3H), 1.53( s, 9H), 1.30 (s, 9H)

Elemental analysis is C ₁₅ H ₂₄ N ₄ O ₄

Calculated: C, 55.54; H, 7.46; N, 17.27

Experimental values: C, 55.36; H, 7.48; N, 17.06

Rf1: 0.64, Rf2: 0.79

Developing solvent for TLC: Rf1 (ethyl acetate/n-hexane=1/2), Rf2 (methanol/chloroform=2/98)

HPLC elution time: 26.7min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: a linear concentration gradient of eluent A/B=100/0-20/80 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (40mins.)

Flow rate: 1.0ml/min

(Reference Example 2)

Preparation of N-methyl-N, N'-di-Z-1-amidinopyrazole

Under an argon atmosphere, 40 mg of 60% NaH oil solution was dissolved in 5 mL of anhydrous DMF, and 380 mg of a commercially available N,N′-di-Z-1-amidinopyrazole solution in 5 mL of anhydrous DMF was added at 0°C, Then stir for 10 minutes. 125 µL of methyl iodide was further added thereto, and the mixture was stirred at room temperature for 15 hours. Then the solvent was evaporated, the residue was dissolved in AcOEt, and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying over _Na2SO4 , the solvent was concentrated to give 393 mg _of crude product. From 170 mg of this crude product, 152 mg (yield 89.5%) of N-methyl-N,N'- Di-Z-1-amidinopyrazole.

¹ H NMR (300MHz, CDCl ₃ ): δ7.97(br s, 1H), 7.61(d, 1H, J=1.0Hz), 7.37-7.32(m, 4H), 7.29-7.26(m, 4H), 7.16-7.13(m, 2H), 6.36(dd, 1H, J=2.8, 1.6Hz), 5.18(s, 2H), 5.04(s, 2H), 3.22(s, 3H)

Elemental analysis is C ₂₁ H ₂₀ N ₄ O ₄

Calculated: C, 64.28; H, 5.14; N, 14.28

Experimental values: C, 64.09; H, 5.24; N, 14.43

Rf1: 0.50, Rf2: 0.86

Developing solvent for TLC: Rf1 (ethyl acetate/n-hexane=1/2), Rf2 (methanol/chloroform=2/98)

HPLC elution time: 28.9min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: a linear concentration gradient of eluent A/B=100/0-20/80 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (40mins.)

Flow rate: 1.0ml/min

[Example 5]

(Synthetic Method E): Preparation of [Arg(Me)9]MS10 (Compound No. 82)

Using 480 mg of Fmoc-Phe-Rink Amide MBHA resin obtained by introducing Fmoc-Phe into a commercially available RinkAmide MBHA resin, the peptide chain was extended on ABI433A to obtain 1080 mg of Boc-Tyr( ^But )Asn( Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheGlyLeuOrn(Mtt)Phe-Aink Amide MBHA resin. To 540 mg of the peptide was added 10 mL of TFA/TIS/DCM (1/5/94) and the mixture was shaken for 50 minutes. The resin is washed and then dried. To 2/5 volume of this resin were added 2 mL of DMF, 49 mg of N-methyl-N,N'-di-Boc-1-amidinopyrazole obtained in Reference Example 1, and 87 µL of DIEA, and the mixture was shaken 15 hours yielded 220 mg of Boc-Tyr( ^But )Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheGlyLeuArg(Boc ₂ , Me)Phe-Rink Amide MBHA resin. To 50 mg of the peptide, 1 mL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added, and the mixture was stirred for 2 hours. Diethyl ether was further added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution, and the extract was filtered to remove the resin. Afterwards, using preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20×150 mm), the eluent according to the ratio of eluent A/B: 74/26-64/36: 0.1 %TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (30 minutes). Fractions containing the product were pooled and lyophilized to give 10.5 mg of a white powder.

Mass spectrum (M+H) ⁺ 1316.5 (calculated 1316.7)

HPLC elution time: 20.1min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

In this example, the N-methyl-N, N'-di-Boc-1 ^- amidinopyrazole used when converting the 9-position amino acid into N ω -methylated Arg is in the presence of N ^ω -methylated Arg It is a useful reagent in the preparation of peptides of ylated Arg, and is also used in general peptides to prepare peptides containing N ^ω -methylated Arg, characterized in that N-methyl-N, N' - Reaction of di-Boc-1-amidinopyrazole with Orn in the peptide followed by deprotection.

In addition, not only the ^Nω -methylated Arg-containing peptides obtained in Examples, but also general peptides, the stability in blood can be improved by converting Arg to ^Nω -methylated Arg. Therefore, the side chain substituents of N ^ω -methylated Arg are suitable for a method of improving stability in blood, which comprises converting Arg in a peptide to N ^ω -methylated Arg.

In addition, a method for improving stability in blood can be provided, which comprises introducing 1 or 2 (preferably 1) alkyl groups, preferably C _1-4 alkyl groups, more preferably methyl groups, into the side of Arg of Arg-containing peptides chain. The Arg-containing peptides include, for example, peptides having a peptide fragment characterized by the structure -Arg-XXX-, wherein XXX represents an amino acid having an optionally substituted aromatic ring group in the side chain, preferably Phe , Trp, Tyr, etc.

Peptides containing N ^ω -methylated Arg can be prepared using not only N-methyl-N,N'-di-Boc-1-amidinopyrazole but also N -Methyl-N, N'-bis-bis-Z-1-amidinopyrazole prepared.

[Example 6]

(Synthetic Method F): Preparation of [6Ψ7, CSNH]MS10 (Compound No. 166)

503 mg of HCl H-Gly- ^OBut was dissolved in 10 mL of DMF, 1162 mg of Fmoc-Phe, 608 mg of HOBt, 1874 mg of PyBOP, and 784 μL of DIEA were added at 0°C, followed by stirring for 4 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying with Na ₂ SO ₄ , the solvent was concentrated and ether-petroleum ether was added to obtain 1.48 g (yield 99%) of Fmoc-PheGly- ^OBut as a precipitate. After dissolving 250 mg of the product in 10 mL of toluene, 404 mg of Lawesson's reagent was added to the solution, followed by stirring at 80°C for 2 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was then washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying _{over Na2SO4} , the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added to the eluate to obtain 207 mg (yield 80%) of Fmoc-PheΨ(CSNH)Gly- ^OBut as a precipitate. To 103 mg of product was added TFA/ _H2O (95/5) and the mixture was stirred for 1 hour. After the solvent was concentrated, diethyl ether was added to obtain 82.4 mg (yield 90%) of Fmoc-PheΨ(CSNH)Gly-OH as a precipitate. Use Fmoc-Phe-PAL resin, which is obtained by introducing Fmoc-Phe into commercially available PAL resin, and use ABI433A to extend the peptide chain to obtain 80 mg of Fmoc-LeuArg(Pbf)Phe-PAL resin, and then the extended product is de-Fmoc Protect. Then 35 mg of Fmoc-PheΨ(CSNH)Gly-OH, 47 mg of PyBrop, 14 mg of HOAt, and 35 μL of DIEA were added to the resin, followed by shaking for 15 hours. After the resin was washed, the peptide chain was extended with ABI433A to obtain Boc-Tyr( ^But )Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheΨ(CSNH)GlyLeuArg(Pbf)Phe-PAL resin. To 15 mg of the product was added 200 μL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5), followed by stirring for an additional 2 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC utilizing YMCD-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 77/23-57/43: 0.1% TFA - Water and eluent B: acetonitrile with 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were pooled and lyophilized to give 1.0 mg of a white powder.

Mass spectrum (M+H) ⁺ 1318.7 (calculated 1318.6)

HPLC elution time: 20.8min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

[Example 7]

(Synthetic Method G): Preparation of [AzaGly7]MS10 (Compound No. 176)

Using 321 mg of Fmoc-Phe-PAL resin obtained by introducing Fmoc-Phe into commercially available PAL resin, the peptide chain was extended on ABI433A to obtain 80 mg of Fmoc-LeuArg(Pbf)Phe-PAL resin, thus This extension was de-Fmoc protected. After adding 2 mL of THF and 16 mg of CDI, the mixture was shaken for 2 hours. Afterwards 6 μL of hydrazine monohydrate was added to the mixture. The resin was washed after shaking the mixture for 1 hour. After adding 39 mg of Fmoc-Phe, 93 mg of PyBrop, 27 mg of HOAt, and 105 μL of DIEA to the system, it was shaken for 2 hours. After washing the resin, the peptide chain was elongated on ABI 433A to give Boc-Tyr( ^But )Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheAzaGlyLeuArg(Pbf)Phe-PAL resin. After adding 1 mL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) to 25 mg of the product, it was shaken for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC D-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 74/26-64/36: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (30 minutes). Fractions containing the product were pooled and lyophilized to give 5.5 mg of a white powder.

Mass spectrum (M+H) ⁺ 1303.3 (calculated 1303.6)

HPLC elution time: 18.9min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

[Example 8]

(Synthetic Method H): Preparation of [D-Tyr1, AzaGly7, Arg(Me)9]MS10 (Compound No. 232)

Fmoc-Phe, Fmoc-Orn (Mtt) were introduced into the commercially available RinkAmide MBHA resin of 4g (0.55mmol/g) to prepare Fmoc-Orn (Mtt)-Phe-Rink Amide MBHA resin, and 50mL of TFA/TIS/DCM ( 1/5/94) was added to the resin, followed by shaking for 50 minutes. After washing the resin, 40 mL of DCM and 2.27 g of N-methyl-N,N'-di-Boc-1-amidinopyrazole prepared in Reference Example 1 were added to the resin. DIEA was added to the mixture to adjust the pH of the solution to 9. The mixture was shaken for 15 hours to obtain 4.74 g of Fmoc-Arg(Boc ₂ , Me)Phe-Rink Amide MBHA resin. Separately, 145 mg of Fmoc-NHNH ₂ HCl was suspended in 10 mL of THF. Under ice-cooling, 89 mg of CDI and 87 mL of DIEA were added to the suspension, followed by stirring at room temperature for 1 hour. To the mixture was added 5 mL of a solution obtained by dissolving 224 mg of H-Leu- ^OBut HCl in 5 mL of DMF under ice-cooling. From returning to room temperature, the mixture was stirred for an additional 18 hours. After the solvent was evaporated, the residue was dissolved in AcOEt and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography to obtain 230 mg (yield 99%) of Fmoc-AzaGly-Leu- ^OBut . To 187 mg of the product was added 10 mL of TFA/H ₂ O (9/1), followed by stirring for 1 hour. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with saturated aqueous NaCl. After drying with Na ₂ SO ₄ , the solvent was concentrated and diethyl ether was added to obtain 143 mg of Fmoc-AzaGly-Leu-OH as a precipitate (yield 87%). The obtained Fmoc-AzaGly-Leu-OH and Trt-Phe were introduced into Fmoc-Arg(Boc ₂ , Me)Phe-Rink Amide MBHA resin. To the obtained Trt-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)Phe-Rink Amide MBHA resin was added 50 mL of TFA/TIS/DCM (1/5/94), and the mixture was shaken for 50 minutes. After the resin was washed and neutralized, Fmoc-Ser( ^But ) was introduced thereinto, followed by Fmoc-Asn(Trt). Using 80.3 mg of the obtained Fmoc-Asn(Trt)Ser( ^But )Phe-AzaGly-LeuArg(Boc ₂ , Me)Phe-Rink AmideMBHA resin, the peptide chain was extended to obtain 97.2 mg of H- _D -Tyr(But ⁾ Asn (Trt)Trp(Boc)Asn(Trt)Ser( ^But )Phe-AzaGly-LeuArg( _Boc2 ,Me)Phe-Rink Amide MBHA resin.

To the obtained resin, 1 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added, followed by stirring for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMCSH-343-5 S-5, 120A column (20×250mm), using eluent according to the ratio of eluent A/B: 76/24-66/34: 0.1% TFA- Water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were pooled and lyophilized to give 11.7 mg of a white powder.

Mass spectrum (M+H) ⁺ 1317.0 (calculated 1317.6)

Elution time of HPLC: 21.0min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

[Example 9]

(Synthetic Method I): Preparation of des(1-3)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9]MS10 (Compound No. 322)

After de-Fmoc protection of 48.2 mg of Fmoc-Asn(Trt)Ser( ^But )Phe-AzaGly-LeuArg(Boc ₂ , Me)Phe-Rink Amide MBHA resin prepared in Example 8, the resin was treated with 15.2 mg Commercially available 3-(3-pyridyl)propionic acid, 15.9 μL of DIPCDI and 200 μL of 0.5M HOAt/DMF were treated at room temperature for 90 minutes. After the obtained resin was washed and dried, 1 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added to the resin, followed by further stirring for 90 minutes. Diethyl ether was added to the reaction solvent, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC SH-343-5 S-5, 120A column (20×250mm), using eluent according to the ratio of eluent A/B: 80/20-60/40: 0.1% TFA - Water and eluent B: acetonitrile with 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were pooled and lyophilized to give 6.0 mg of a white powder.

Mass spectrum (M+H) ⁺ 987.4 (calculated 987.5)

HPLC elution time: 8.1min

Elution conditions:

Column YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=80/20-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 10]

(Synthetic Method J): Preparation of des(1-2)-amidino-[AzaGly7, Arg(Me)9]MS10 (Compound No. 273)

After introducing Fmoc-Trp(Boc) into 48.2 mg of Fmoc-Asn(Trt)Ser( ^But )Phe-AzaGly-LeuArg(Boc ₂ , Me)Phe-Rink Amide MBHA resin prepared in Example 8, The Fmoc protection of the resin was removed to obtain H-Trp(Boc)Asn(Trt)Ser( ^But )Phe-AzaGly-LeuArg(Boc ₂ , Me)Phe-Rink Amide MBHA resin. The obtained resin was treated with 29.3 mg of N, N'-two-Boc-1-amidinopyrazole and 34.8 μL of DIEA in DMF for 14 hours to obtain amidino-Trp(Boc)Asn(Trt)Ser( ^But ) Phe-AzaG1y-LeuArg (Boc ₂ , Me) Phe-Rink Amide MBHA resin. After the obtained resin was washed and dried, 1 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added and stirred for another 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC SH-343-5 S-5, 120A column (20×250mm), using eluent according to the ratio of eluent A/B: 78/22-58/42: 0.1% TFA - Water and eluent B: acetonitrile with 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were pooled and lyophilized to give 0.6 mg of a white powder.

Mass spectrum (M+H) ⁺ 1082.3 (calculated 1082.6)

HPLC elution time: 11.4min

Elution condition:

Column: YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=80/20-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 11]

(Synthetic Method K): Preparation of [6Ψ7, NHCO, D-Tyr1, Arg(Me)9]MS10 (Compound No. 319)

5.99 g of Z-Phe was dissolved in 30 mL of MeCN, 3.94 g of HONB and 4.59 g of WSCD HCl were added to the solution at 0° C., followed by stirring at room temperature for 4 hours. While keeping the temperature at 0° C., 3.4 mL of 25% NH ₃ aqueous solution and 10 mL of DMF were added to the mixture, followed by further stirring for 4 hours. After evaporation of the solvent, the residue was dissolved in AcOEt, and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was concentrated and diethyl ether was added to give 1.48 g (yield 99%) of Z-Phe-NH ₂ as a precipitate. After dissolving 1.94 g of [bis(trifluoroacetoxy)iodo]benzene in 20 mL of MeCN and 5 mL of H ₂ O, 890 mg of the above-prepared Z-Phe-NH ₂ and 972 μL of pyridine, and stirred at room temperature for 15 hours. After the solvent was concentrated, the concentrate was subjected to liquid-liquid separation with ether-1N aqueous HCl solution, and then the 1N aqueous HCl solution layer was concentrated and then dried. Half of the volume was dissolved in 5 mL of DMF, and 486 μL of mono-tert-butylmalonate and 540 mg of HOBt were added to the solution. Then, 2.08 g of PyBOP and 1394 μL of DIEA were added to the mixture at 0° C., followed by stirring at room temperature for 15 hours. After evaporation of the solvent, the residue was dissolved in AcOEt, and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying _{over Na2SO4} , the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added thereto to obtain 304 mg (yield 33%) of Z-PheΨ(NHCO)Gly- ^OBut as a precipitate. After 154 mg of the product was dissolved in 20 mL of MeOH, 10% Pd—C was added to the solution, and catalytic hydrogenation was carried out under hydrogen flow for 2 hours. After removing the catalyst by filtration, the solvent was concentrated to dryness. The residue was dissolved in 10 mL of MeCN, and 152 mg of Fmoc-Osu and 78 μL of DIEA were added to the solution, followed by further stirring for 15 hours. After evaporation of the solvent, the residue was taken up with AcOEt and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ , then saturated aqueous NaCl. After drying with Na ₂ SO ₄ , the solvent was concentrated and ether-petroleum ether was added to give 127 mg (68% yield) of Fmoc-PheΨ(NHCO)Gly- ^OBut as a precipitate. Fmoc-Leu was introduced into 63 mg of Fmoc-Arg(Boc ₂ , Me)Phe-Rink Amide MBHA resin prepared in Example 10. After deprotection of Fmoc, Fmoc-PheΨ(NHCO)Gly-OH (obtained by 25 mg of Fmoc-PheΨ(NHCO)Gly- ^OBut and TFA for 3 minutes), 300 μL of 0.5M HOAt, 78 mg of PyAOP, and 52 μL of DIEA, followed by shaking for 6 hours. After washing the resin, 2 mL of DMF, 9 μL of DIEA, and 12 μL of Ac ₂ O were added to the resin, followed by shaking for 30 minutes. After the resin was washed, the peptide chain was extended on ABI433A to obtain Boc-D-Tyr( ^But )Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheΨ(NHCO)GlyLeuArg(Boc ₂ , Me)Phe -Rink Amide MBHA resin. To 34 mg of the product, 200 μL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added and stirred for another 2 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC D-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 76/24-66/34: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (30 minutes). Fractions containing the product were pooled and lyophilized to give 0.7 mg of a white powder.

Mass spectrum (M+H) ⁺ 1316.3 (calculated 1316.7)

HPLC elution time: 18.7min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-0/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

[Example 12]

(Synthetic Method L): Preparation of [N((CH ₂ ) ₃ Gn)Gly9]-MS10 (Compound No. 218)

Using 192 mg of Fmoc-Phe-Rink Amide MBHA resin, the peptide chain was extended on ABI433A to obtain Fmoc-GlyPhe-Rink Amide MBHA resin. After 1/4 volume of the resultant was deFmoc-protected, 2 mL of DMF, 50 μL of AcOH, 5 mg of Boc-β-Ala-H, and 16 mg of NaBH ₃ CN were added thereto, and the mixture was shaken for 30 minutes. After the resin was washed, 71 mg of Fmoc-Leu, 56 mg of CIP, 27 mg of HOAt, and 105 mL of DIEA were added thereto, followed by shaking for 15 hours. After washing the resin, the peptide chain was extended on ABI433A to give Z-Tyr(Bzl)Asn(Trt)Trp(Boc)Asn(Trt)Ser( ^But )PheGlyLeuN((CH ₂ ) ₃ NHBoc)GlyPhe-Rink Amide MBHA resin . 1 mL of TFA/PhOH/H ₂ O/TIS/EDT (87.5/5/2.5/2.5/2.5) was added to the product and the mixture was shaken for 2 hours. The resin was removed by filtration and concentrated, and diethyl ether was added to the concentrate. Half the volume of the obtained precipitate was dissolved in 500 μL of DMF, 9 mg of 1H-pyrazole-1-carboxamidine hydrochloride and 22 mL of DIEA were added to the solution, followed by stirring for 15 hours. The solvent was evaporated and diethyl ether was added to the precipitate. Under ice-cooling, 60 μL of PhSMe, 56 μL of m-cresol, 26 μL of EDT, 337 μL of TFA, and 65 μL of TMSBr were added to the mixture, followed by stirring for 2 hours. After distilling off the solvent, diethyl ether was added to the residue, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC D-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 74/26-64/36: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were pooled and lyophilized to give 1.8 mg of a white powder.

Mass spectrum (M+H) ⁺ 1302.5 (calculated 1302.7)

HPLC elution time: 18.6min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (35mins.)

Flow rate: 1.0ml/min

[Example 13]

(Synthetic Method M): Preparation of MS10 (Compound No. 3)

Commercially available p-methyl BHA resin (0.77 mmole/g resin) was placed in the reaction tank of the peptide synthesizer ABI430A. According to the Boc-strategy (DCC-HOBt) peptide synthesis method, Boc-Phe.Boc-Arg(Tos), Boc-Leu.Boc-Gly, Boc-Phe.Boc-Ser(Bzl), Boc-Asn.Boc- Trp(For) and Boc-Asn.Boc-Tyr(Br-Z) were sequentially introduced into the resin to obtain the desired protected peptide resin. 0.11 g of this resin was stirred at 0° C. for 60 minutes in 10 ml of anhydrous hydrogen fluoride containing 1 ml of p-cresol and 1.2 ml of 1,4-butanediol. Hydrogen fluoride was then distilled off under reduced pressure. Diethyl ether was added to the residue, and the precipitate was filtered. A 50% aqueous acetic acid solution was added to the precipitate for extraction, and insoluble matter was removed. After the extract was sufficiently concentrated, the concentrate was supplied to a Sephadex (trade name) G-25 column (2.0×80 cm) filled with a 50% aqueous acetic acid solution, followed by development with the same solvent. The main fractions were collected and lyophilized to obtain 40 mg of white powder. Half the volume of the powder was supplied to a column (2.6×60 cm) filled with LiChroprep (trade name) RP-18, and washed with 200 ml of water containing 0.1% TFA. Then, 300 ml of 0.1% TFA-water and 300 ml of 33% acetonitrile containing 0.1% TFA were used for linear concentration gradient elution. The main fractions were collected and lyophilized to obtain 2.2 mg of the target peptide.

Mass spectrum (M+H) 1302.5 (calculated value 1302.6)

HPLC elution time: 18.7min

Elution condition:

Column: Wakosil-II 5C18T 4.6×100mm

Eluent: A linear concentration gradient of eluent A/B=95/5-45/55 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.) Flow rate: 1.0ml/min

[Example 14]

(Synthetic Method N): Preparation of des(1-3)-2-(indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9]MS10 (Compound No. 279)

The Fmoc-Asn(Trt)Ser( ^But )PheAzaGlyLeuArg(Me,Boc ₂ )Phe-Rink-Amide MBHA resin prepared in Example 8 was de-Fmoc-protected. To 64 mg (20 μmol) of H-Asn(Trt)Ser( ^But )PheAzaGlyLeuArg(Me, Boc ₂ )Phe-Rink Amide MBHA resin, 1.5 mL of THF and 13 mg of CDI were added, followed by shaking for 2 hours. After adding thereto 32 mg of tryptamine hydrochloride, 28 μL of DIEA, and 500 μL of DMF, the mixture was shaken for 24 hours. After washing the resin again, 2-(indol-3-yl)ethylcarbamoyl-Asn(Trt)Ser( ^But )PheAzaGlyLeuArg(Me, _Boc2 )Phe-Rink Amied MBHA resin was obtained. To 15 mg of the product was added 200 μL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5), followed by stirring for 2 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC D-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 69/31-59/41: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were pooled and lyophilized to give 1.1 mg of a white powder.

Mass spectrum (M+H) ⁺ 1040.2 (calculated 1040.5)

HPLC elution time: 20.1min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-0/50 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 15]

Preparation of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA Resin

Commercially available RinkAmide MBHA resin 5g (0.4mmol/g) was swollen in DMF and treated with 50ml of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc group. After washing the resulting resin with DMF, it was treated with 4.213 g (8 mmol) of Fmoc-Trp(Boc)-OH, 1.272 mL (8 mmol) of DIPCDI and 16 mL (8 mmol) of 0.5M HOAt/DMF solution at room temperature for 90 minutes, Introduce Trp(Boc) to obtain Fmoc-Trp(Boc)-Rink Amide MBHA resin. By the same method, introduce Orn (Mtt) to obtain 2 mmol of Fmoc-Orn (Mtt)-Trp (Boc)-Rink Amide MBHA resin. After the obtained resin was washed and swollen with DCM, 50 mL of TFA/TIS/DCM (1/5/94) was added, the mixture was shaken for 10 minutes, and the solvent was evaporated. This operation was repeated until the yellow coloration caused by free Mtt groups in the solution disappeared when TFA/TIS/DCM (1/5/94) solution was added, thus removing the Mtt groups.

The resulting Fmoc-Orn-Trp(Boc)-Rink AmideMBHA resin was neutralized with a 5%-DIEA/DCM solution. After washing with DCM, 25 mL of DCM-TFE (4:1) and 1.946 g (6 mmol) of N-methyl-N,N'-di-Boc-1- amidinopyrazole. DIEA was added to the mixture to adjust the pH of the solution to 10, and the mixture was shaken for 15 hours to obtain 6.195 g of Fmoc-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. In the same manner as above, Fmoc-Leu was introduced into the obtained resin. The resin was split in half and the Fmoc group was removed from the resulting Fmoc-Leu-Arg( _Boc2 ,Me)-Trp(Boc)-Rink Amide MBHA resin (1 mmol) to give H-Leu-Arg( _Boc2 ,Me )-Trp(Boc)-Rink Amide MBHA resin (1 mmol).

Separately, 1.745 g (6 mmol) of Fmoc-NHNH ₂ HCl was suspended in 20 mL of DMF-THF (4:1). Under ice-cooling, 973 mg (6 mmol) of CDI and 2.09 mL (12 mmol) of DIEA were added to the suspension, followed by stirring at room temperature for 1 hour. The resulting reaction solution was added to the aforementioned H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin, followed by stirring at room temperature for 15 hours. After the reaction, the resin was washed and dried to obtain 3.314 g of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin.

[Example 16]

(Synthetic Method O): Preparation of des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 385)

After swelling 100 mg (0.03 mmol) of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-RinkAmide MBHA resin in DMF, the resin was treated with 2 ml of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc group. After the resulting resin was washed with DMF, the resin was mixed with 77.5 g (0.2 mmol) of Fmoc-Phe-OH, 31.8 μL (0.2 mmol) of DIPCDI and 0.4 mL (0.2 mmol) of 0.5M HOAt/DMF solution at room temperature Under treatment for 90 minutes, Phe was introduced. By the same method, Ser(tBu) and Asn(Trt) were introduced to obtain Fmoc-Asn(Trt)-Ser( ^t Bu)-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)- Rink Amide MBHA resin. The resulting resin was deFmoc-protected and reacted with 77.6 mg (0.2 mmol) of Fmoc- _D -Pya(4)-OH, 104.2 mg (0.2 mmol) of PyAOP, 400 μL (0.2 mmol) of 0.5M HOAt/DMF And 174.2 μL (0.2 mmol) of DIEA was treated at room temperature for 90 minutes to introduce _D -Pya(4), followed by _D -Tyr( ^t Bu), and then deprotected. 135 mg of H- _D -Tyr( ^t Bu) _-D -Pya(4)-Asn(Trt)-Ser( ^t Bu)-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc ) - Rink Amide MBHA resin.

To the obtained resin, 1 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added, followed by stirring for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process was repeated twice for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use the preparative HPLC using YMCPack R&D-ODS-5-B S-5, 120A column (30×250mm), adopt the eluent according to the ratio of eluent A/B: 79/21-69/31: 0.1 %TFA-water and eluent B: acetonitrile containing 0.1% TFA, with a flow rate of 15 ml/min for linear concentration gradient elution (60 minutes). Fractions containing product were pooled and lyophilized. The obtained white powder was dissolved in 10 mL of water, and 100 μL of ion exchange resin BioRAD AG1×8 AcO ^- form was added to the solution. The reaction solution was left for 1 hour while stirring the solution manually from time to time. The solution was filtered through a membrane filter to remove the resin to obtain 6.6 mg of a white powder as acetate.

Mass spectrum (M+H) ⁺ 1204.5 (calculated 1204.6)

HPLC elution time: 8.2min

Elution condition:

Column YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=80/20-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 17]

(Synthetic Method P): Preparation of des(1-6)-dibenzylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 393)

After swelling 35.2 mg (0.015 mmol) of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-RinkAmide MBHA resin in DMF, the resin was treated with 2 ml of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc group. Separately, 19.2 µL (0.1 mmol) of dibenzylamine was dissolved in THF. Under ice-cooling, 16.2 mg (0.1 mmol) of CDI and 2.6 μL (0.015 mmol) of DIEA were added to the solution, followed by stirring at room temperature for 1 hour. After deprotection of Fmoc, the resulting solution was added to H-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink AmideMBHA resin, followed by stirring at room temperature for 15 hours.

To the obtained Bzl ₂ NCO-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink AmideMBHA resin, add 1 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/ 5/5/5/2.5/2.5), then shake the mixture for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process was repeated twice for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC SH-343-5 S-5, 120A column (20×250mm), using eluent according to the ratio of eluent A/B: 63/37-53/47: 0.1% TFA - Water and eluent B: acetonitrile containing 0.1% TFA, eluted with a linear concentration gradient at a flow rate of 8 ml/min (60 minutes). Fractions containing product were pooled and lyophilized. The obtained white powder was dissolved in 10 mL of water, and 100 μL of ion exchange resin BioRAD AG1×8 AcO ^- form was added to the solution. The reaction solution was left for 1 hour while stirring the solution manually occasionally. The solution was filtered through a membrane filter to remove the resin to obtain 2.2 mg of a white powder as acetate.

Mass spectrum (M+H) ⁺ 768.7 (calculated 768.4)

HPLC elution time: 16.9min

Elution condition:

Column YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=80/20-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 18]

(Synthetic Method Q): Preparation of des(1-5)-benzoyl-[6Ψ7, CH ₂ O, Arg(Me)9, Trp10]MS10 (Compound No. 421)

After dissolving 1.80 g of Z-Phe in 20 mL of MeOH, 73 mg of DMAP and 1.38 g of WSCD HCl were added to the solution at 0°C, followed by stirring at 4°C for 12 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was then washed with 1 N aq. HCl, sat. aq. NaHCO ₃ , and sat. aq. NaCl. After drying _{over Na2SO4} , the solvent was concentrated to give Z-Phe-OMe as an oil. After it was dissolved in 20 mL of anhydrous THF, 196 mg of LiBH ₄ was added to the solution, followed by stirring at room temperature for 15 hours. The solvent was concentrated, the concentrate was dissolved in AcOEt, and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was concentrated and ether-petroleum ether was added to the concentrate to obtain 1.45 g (yield 85%) of Z-Phe-ol as a precipitate. After suspending 60 mg of 60% NaH in 10 mL of anhydrous THF, 285 mg of Z-Phe-ol, 264 mg of 18-crown-6 (18-crown-6) and 1.48 mL of tert-butyl bromoacetate. While returning the temperature to room temperature, the mixture was shaken for 15 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in AcOEt, and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography to afford 217 mg (54% yield) of Z-PheΨ(CH ₂ O)Gly-OBut ^{as an oil} . After 160 mg of Z-PheΨ(CH ₂ O)Gly- ^OBut was dissolved in 20 mL of MeOH, 10% Pd—C was added to the solution, followed by catalytic hydrogenation under nitrogen flow for 3 hours. The catalyst was removed by filtration, and the solvent was concentrated, followed by drying. The concentrate was dissolved in 15 mL of DCM, and 114 mg of Fmoc-Cl and 139 μL of DIEA were added to the solution, followed by stirring for 12 hours. After evaporation of the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying _{over Na2SO4} , the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added thereto to obtain 150 mg (yield 77%) of Fmoc-PheΨ(CH ₂ O)Gly- ^OBut as a precipitate. To the precipitate were added 31 mg (15 μmol) of H-LeuArg(Me, Boc ₂ )Trp(Boc)-Rink Amide MBHA resin, 19 mg of Fmoc-PheΨ(CH ₂ O)Gly- OH (obtained from Fmoc-PheΨ(CH ₂ O)Gly- ^OBut treated with 50% TFA/DCM for 1 hour), 180 μL of 0.5M HOAt, 42 mg of PyBrop and 47 μL of DIEA. The mixture was shaken for 18 hours. After washing the resin, add 5 mL of 20% piperidine/DMF to the resin, and stir at room temperature for 30 minutes. After washing the resin, add 9 μL of benzoyl chloride, 13 μL of DIEA and 1 mL of DMF to the resin, and then stir at Stir for 2 hours. After the resin was washed and dried, 200 μL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added to the resin, followed by further stirring for 2 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC utilizing YMCD-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 75/25-65/35: 0.1% TFA - Water and eluent B: acetonitrile with 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were pooled and lyophilized to give 2.5 mg of a white powder.

Mass spectrum (M+H) ⁺ 782.2 (calculated 782.4)

HPLC elution time: 22.1min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-0/50 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 19]

(Synthetic Method R): Preparation of des(1-7)-dibenzylaminocarbamoylacetyl-[Arg(Me)9, Trp10]MS10 (Compound No. 434)

After 1.54 mL of mono-tert-butylmalonate, 1.08 g of fluorenylmethanol, and 61 mg of DMAP were dissolved in 20 mL of DCM20, 1.15 g of WSCD HCl was added to the solution, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in AcOEt. The solution was then washed with 1 N aq. HCl, sat. aq. NaHCO ₃ , and sat. aq. NaCl. After drying over Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography to obtain 1.62 g (96% yield) of tert-butylfluorenylmethylmalonate. 61 mg of tert-butylfluorenylmethylmalonate was dissolved in 20 mL of TFA and the solution was shaken at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in AcOEt, followed by washing with saturated aqueous NaCl. After drying _{over Na2SO4} , the solvent was concentrated and purified by flush column chromatography to afford 850 mg (67% yield) of mono-fluorenylmethylmalonate. After adding 5 mL of 20% piperidine/DMF to 46 mg (15 μmol) of Fmoc-LeuArg(Me, Boc ₂ ) Trp(Boc)-Rink Amide MBHA resin obtained in the same manner as in Example 15, the solution Shake for 30 minutes at room temperature. After washing the resin, 42 mg mono-fluorenylmethylmalonate, 70 mg PyBrop, 300 μL of 0.5M HOAt/DMF, 52 μL of DIEA, and 1 mL of DMF were added to the resin and the mixture was shaken for 15 hours. This process was repeated twice, and 8 μL Ac ₂ O, 5 μL DIEA, and 2 mL DCM were added, followed by stirring at room temperature for 30 minutes. After the resin was washed and dried, 5 mL of 20% piperidine/DMF was added to half of the resin, followed by stirring at room temperature for 30 minutes. After washing the resin, 13 mg of dibenzylhydrazine, 28 mg of PyBrop, 120 μL of 0.5M HOAt/DMF, 21 μL of DIEA, and 1 mL of DMF were added to the resin, followed by shaking for 15 hours. After the resin was washed and dried, 200 μL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added to the resin, followed by stirring for another 2 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC D-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 83/17-63/37: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution (120 minutes). Fractions containing the product were pooled and lyophilized to give 21.6 mg of a white powder.

Mass spectrum (M+H) ⁺ 767.6 (calculated 767.4)

HPLC elution time: 14.5min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-30/70 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 20]

(Synthetic Method S): Preparation of des(1-5)-4-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 436)

After 340.1 mg (0.1 mmol) of Fmoc-AzaGly-Leu-Arg(Boc ₂ ,Me)-Trp(Boc)-RinkAmide MBHA resin was swelled in DMF, the resin was treated in 20 ml of 20% piperidine/DMF solution 20 minutes to remove the Fmoc group. The resulting resin was washed with DMF and treated with 155.0 mg (0.4 mmol) of Fmoc-Phe-OH, 63.6 μL (0.4 mmol) of DIPCDI and 0.8 mL (0.4 mmol) of a 0.5M HOAt/DMF solution at room temperature for 90 minutes, Used to introduce Phe. After the obtained Fmoc-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin was deprotected by Fmoc, it was mixed with 49.2mg (0.4mmol) of 4-pyridinecarboxylate at room temperature Acid, 63.6 μL (0.4 mmol) of DIPCDI and 0.8 mL (0.4 mmol) of 0.5M HOAt/DMF solution were treated for 90 minutes. The resin was then washed and dried to obtain 353.5 mg of 4-pyridinecarbonyl-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. To the obtained resin was added 3.5 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5), and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process was repeated twice for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use the preparative HPLC using YMC Pack R & D-ODS-5-B S-5, 120A column (30×250mm), adopt the elution according to the ratio of eluent A/B: 79/21-69/31 Solution: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution was performed at a flow rate of 15 ml/min (60 minutes). Fractions containing product were pooled and lyophilized. The resulting white powder was dissolved in 6 mL of water, and 200 μL of ion exchange resin BioRAD AG1×8 AcO ^- form was added to the solution. The reaction solution was left for 1 hour while stirring the solution manually from time to time. The solution was filtered through a membrane filter to remove the resin to obtain 21.6 mg of a white powder as acetate.

Mass spectrum (M+H) ⁺ 797.8 (calculated 797.4)

HPLC elution time: 8.8min

Elution conditions:

Column YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient elution of eluent A/B=80/20-30/70 was used. 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 21]

(Synthetic Method T): Preparation of des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 499)

After swelling 170.1 mg (0.05 mmol) of Fmoc-AzaGly-Leu-Arg(Boc ₂ ,Me)-Trp(Boc)-RinkAmide MBHA resin in DMF, the resin was treated with 5 ml of 20% piperidine/DMF solution 20 minutes to remove the Fmoc group. The resulting resin was washed with DMF and treated with 77.5 mg (0.2 mmol) of Fmoc-Phe-OH, 31.8 μL (0.2 mmol) of DIPCDI, and 0.4 mL (0.2 mmol) of a 0.5 M HOAt/DMF solution for 90 min at room temperature Used to introduce Phe. By the same method, Ser(tBu) and Asn(Trt) were introduced to obtain Fmoc-Asn(Trt)-Ser( ^t Bu)-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. After deFmoc-deprotecting the resulting resin, it was treated with 30.0 mg (0.2 mmol) of phenylpropionic acid, 31.8 μL (0.2 mmol) of DIPCDI, and 0.4 mL (0.2 mmol) of a 0.5 M HOAt/DMF solution at room temperature 90 minutes. Thereafter, the resin was washed and dried to obtain 209.6 mg of 3-phenylpropionyl-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. To the obtained resin was added 1.5 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5), and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process was repeated twice for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC SH-343-5 S-5, 120A column (20×250mm), using eluent according to the ratio of eluent A/B: 71/29-61/39: 0.1% TFA - Water and eluent B: acetonitrile containing 0.1% TFA, eluted with a linear concentration gradient at a flow rate of 8 ml/min (60 minutes). Fractions containing product were pooled and lyophilized. Dissolve the resulting white powder in 10 mL of water, and add 125 μL of ion exchange resin BioRAD AG1×8 AcO ^- form to the solution. The reaction solution was left for 1 hour while stirring the solution manually from time to time. The solution was filtered through a membrane filter to remove the resin to obtain 5.2 mg of a white powder as acetate.

Mass spectrum (M+H) ⁺ 1025.3 (calculated 1025.5)

HPLC elution time: 13.6min

Elution conditions:

Column YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient elution of eluent A/B=80/20-30/70 was used. 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 22]

(Synthetic Method U): Preparation of des(1-5)-benzoyl-[AzaPhe6, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 431)

After dissolving 500 mg (2.56 mmol) of benzylhidrazine.2HCl in DCM, the solution was cooled to -78°C on dry ice. Then 727.1 mg (3.33 mmol) of Boc ₂ O and 0.982 ml (5.64 mmol) of DIEA were added to the solution. The dry ice was removed and the mixture was stirred for 30 minutes. After confirming the progress of the reaction by TLC, 327 µl (2.82 mmol) of benzoyl chloride and 580.4 µl (3.33 mmol) of DIEA were added to the mixture, followed by stirring overnight at room temperature. Citric acid crystals were added to the reaction solution, and the mixture was concentrated. A 10% aqueous solution of citric acid was added to the mixture. The precipitated residue was extracted with AcOEt, and the extract was washed with 10% citric acid aqueous solution, 5% NaHCO ₃ aqueous solution and saturated NaCl aqueous solution, and then dried over anhydrous Na ₂ SO ₄ . The resulting residue was crystallized from ether-hexane (1:1) to obtain 435.5 mg of white crystals.

After swelling 46.3 mg (0.015 mmol) of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-NH-Rink Amide MBHA resin in DMF, the resin was mixed with 5 ml of 20% piperidine/ The DMF solution was treated for 20 minutes to remove the Fmoc group. The resulting resin was washed with DMF and treated with 3.65 mg (0.023 mmol) of CDI in THF for 1 hour at room temperature. Separately, 32.6 mg (0.1 mmol) of the above white powder was treated with 0.3 ml of 4N HCl/dioxane for 1 hour. The solvent was then evaporated and the residue was washed with ether. The resulting residue was dissolved in THF, and 17.4 µl (0.1 mmol) of DIEA was added to the solution. The resulting solution was added to the resin, followed by stirring overnight. The resin was washed and dried to obtain 29.5 mg of benzoyl-AzaPhe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-NH-Rink Amide MBHA resin. To the resulting resin, 0.5 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added, and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process was repeated twice for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC using YMC SH-343-5 S-5, 120A column (20×250mm), using eluent according to the ratio of eluent A/B: 66/34-56/44: 0.1% TFA - Water and eluent B: acetonitrile containing 0.1% TFA, eluted with a linear concentration gradient at a flow rate of 8 ml/min (60 minutes). Fractions containing product were collected and lyophilized to give 3.2 mg of a white powder.

Mass spectrum (M+H) ⁺ 797.7 (calculated 797.4)

HPLC elution time: 15.3min

Elution condition:

Column YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient elution of eluent A/B=80/20-30/70 was used. 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 23]

(Synthetic Method V): Preparation of des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, 10Ψ, CSNH]MS10 (Compound No. 548)

Fmoc-Leu-OH was introduced into commercially available 2-chlorotrityl chloride resin. After deprotection of Fmoc, 5 mL of THF and 162 mg of CDI were added to the obtained 403 mg of Fmoc-Leu-O-Clt resin (sub. 0.62 mmol/g). The mixture was shaken for 1 hour. After adding 97 μL of hydrazine monohydrate to the system, the mixture was shaken for 2 hours, after which the resin was washed. 581 mg of Fmoc-Phe, 699 mg of PyBrop, 3 mL of 0.5M HOAt/DMF solution, and 784 μL of DIEA were added to the resin, followed by shaking for 12 hours. After the resin was washed, the peptide chain was extended on ABI433A to obtain 0.47 g of Boc- _D -Tyr( ^But ) _D -Pya(4)Asn(Trt)Ser(But ⁾ PheAzaGlyLeu-O-Clt resin. 10 mL of AcOH/TFE/DCM (1/1/8) was added to the resin, followed by shaking for an additional 30 minutes. The resin was removed by filtration and the solvent was concentrated. The residue was dissolved in chloroform, and the resulting solution was washed with saturated aqueous NaCl. After drying with _Na2SO4 , the solvent was concentrated, and AcOEt-ether was added to the concentrate to obtain 320 mg (yield 98%) of Boc-D-Tyr( ^But )D-Pya(4 ₎ Asn as a precipitate (Trt)Ser( ^But )PheAzaGlyLeu-OH. On the other hand, 5 mL of 4N HCl/AcOEt was added to 264 mg (1 mmol) of Boc-Phe-NH ₂ under ice-cooling, followed by stirring for 30 minutes. The solvent was evaporated, and diethyl ether was added to cause precipitation. The precipitate was dissolved in 20 mL of DMF, and 455 mg of Fmoc-Orn (Boc), 540 mg of HOBt, 382 mg of WSCD.HCl, and 348 μL of DIEA were added to the solution, followed by stirring for 6 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed with 1N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying _{over Na2SO4} , the solvent was concentrated. Diethyl ether-petroleum ether was added to the concentrate to obtain 594.4 mg (yield 99%) of Fmoc-Orn(Boc)-Phe-NH ₂ as a precipitate. Under ice-cooling, 5 mL of 4N HCl/AcOEt was added to 132 mg of the product, followed by stirring for 30 minutes. After distilling off the solvent, diethyl ether was added to obtain 111.1 mg (yield 94%) of Fmoc-Orn-Phe-NH ₂ .HCl as a precipitate. The precipitate was dissolved in 3 mL of chloroform/TFE (3/1), and 194 mg of N-methyl-N,N'-di-Boc-1-amidinopyridine obtained in Reference Example 1 was added to the solution azole and 105 μL of DIEA, followed by stirring for 24 hours. After distilling off the solvent, diethyl ether-petroleum ether was added to obtain 108.5 mg (yield 72%) of Fmoc-Arg(Boc ₂ , Me)-Phe-NH ₂ as a precipitate. 38 mg of the product was dissolved in 5 mL of THF, and 142 mg of Lawesson's reagent was added to the solution, followed by stirring for 15 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed with aqueous NaHCO ₃ , saturated aqueous NaCl. After drying _{over Na2SO4} , the solvent was concentrated. After purification by flushing column chromatography, ether-petroleum ether was added to obtain 18.7 mg (48% yield) of Fmoc-Arg(Me,Boc ₂ )-PheΨ(CSNH)-NH ₂ as a precipitate. To 11 mg of the product was added 1 mL of 10% DEA/DMF, and the mixture was stirred for 2 hours. After distilling off the solvent, the residue was dissolved in 1 mL of DMF, and 18 mg of Boc _-D -Tyr( ^But ) _-D -Pya(4)-Asn(Trt)-Ser( ^But ) prepared in advance was added to the solution. - Phe-AzaGly-Leu-OH, 7.6 mg HOBt, 5.4 mg WSCD.HCl and 4.9 μL DIEA followed by stirring for 15 hours. The solvent was distilled off and diethyl ether was added to the residue to obtain a precipitate. 1 mL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added to the precipitate, and the mixture was stirred for 2 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This process is repeated several times for washing. The residue was extracted with aqueous acetic acid solution and the extract was filtered to remove the resin. Then use preparative HPLC utilizing YMCD-ODS-5-ST S-5 120A column (20×150mm), using eluent according to the ratio of eluent A/B: 82/18-72/28: 0.1% TFA - Water and eluent B: acetonitrile with 0.1% TFA, linear concentration gradient elution (60 minutes). Fractions containing the product were collected and lyophilized to give 0.9 mg of a white powder.

Mass spectrum (M+H) ⁺ 1181.5 (calculated 1181.6)

HPLC elution time: 14.9min

Elution conditions:

Column: Wakosil-II 5C18 HG (4.6×100mm)

Eluent: A linear concentration gradient of eluent A/B=100/0-0/50 was used for elution, 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 24]

(Synthetic Method W): Preparation of Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 550)

After swelling 5 g (0.4 mmol/g) of commercial Rink Amide MBHA resin in DMF, the resin was treated with 50 ml of 20% piperidine/DMF solution for 20 minutes in order to remove the Fmoc groups. After washing the resulting resin with DMF, the resin was treated at room temperature by treating the resin with 4.213 g (8 mmol) of Fmoc-Trp(Boc)-OH, 1.272 mL (8 mmol) of DIPCDI, and 16 mL (8 mmol) of a 0.5 M HOAt/DMF solution For 90 minutes, Trp(Boc) was introduced. According to the same method, Orn (Mtt) was introduced to obtain 2 mmol of Fmoc-Orn (Mtt)-Trp (Boc)-Rink Amide MBHA resin. After the obtained resin was washed with DCM and swelled, 50 mL of TFA/TIS/TFE/DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solvent was evaporated. This operation was repeated until the yellow coloring caused by free Mtt groups in the solution disappeared when TFA/TIS/TFE/DCM (1/5/19/75) solution was added, thus removing the Mtt groups.

The resulting Fmoc-Orn-Trp(Boc)-Rink AmideMBHA resin was neutralized with a 5%-DIEA/DCM solution. After washing with DCM, 25 mL of DCM-TFE (4:1) and 1.946 g (6 mmol) of N-methyl-N,N'-di-Boc-1- amidinopyrazole. DIEA was added to the mixture, the pH of the solution was adjusted to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. Fmoc-Leu was introduced into the resulting resin as described above. The Fmoc group was removed from the resulting Fmoc-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin (2 mmol) to give H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)- Rink Amide MBHA resin (2 mmol).

Separately, 2.326 g (8 mmol) of Fmoc-NHNH ₂ .HCl was suspended in 20 mL of DMF. Under ice-cooling, a suspension of 297 mg (8 mmol) of CDI suspended in 20 mL of THF was added to the suspension, and 2.787 mL (16 mmol) of DIEA was added, followed by stirring at room temperature for 1 hour. The resulting reaction solution was added to the above H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin, and stirred at room temperature for 15 hours. After the reaction, the resin was washed and dried to obtain 6.394 g of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin.

After swelling 3.197 g (1 mmol) of the resulting resin in DMF, the resin was treated with 30 ml of a 20% piperidine/DMF solution for 20 minutes in order to remove the Fmoc group. After washing the resulting resin with DMF, the resin was mixed with 1.806 g (4 mmol) of Trt-Phe-OH. DIEA was treated at room temperature for 90 minutes to obtain Trt-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink AmideMBHA resin Phe. The resulting resin was washed with DCM and after swelling, 30 mL of TFA/TIS/TFE/DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solvent was evaporated. This operation was repeated until the TFA/TIS/TFE/DCM (1/5/19/75) solution was added until the yellow coloration caused by the free Trt groups in the solution disappeared, thus removing the Trt groups. The obtained H-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin was neutralized with 5%-DIEA/DMF solution, and washed with DMF. Afterwards, the resin was treated with 1.590 g (4 mmol) of Fmoc-Thr( ^t Bu)-OH, 0.636 mL (4 mmol) of DIPCDI and 8 mL (4 mmol) of 0.5 M HOAt/DMF at room temperature for 90 minutes to introduce Thr ( ^t Bu). Then, the operation of de-Fmoc protection by treating with 30ml of 20% piperidine/DMF solution for 20 minutes and repeated condensation by the same DIPCDI/HOAt method as introducing Thr( ^tBu ) made Asn(Trt), _D- Trp(Boc) and _D -Tyr( ^t Bu) were introduced to obtain Fmoc- _D -Tyr( ^t Bu)- _D -Trp(Boc)-Asn(Trt)-Thr( ^t Bu) -Phe-AzaGly-Leu-Arg (Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. The resulting resin was treated with 30 ml of a 20% piperidine/DMF solution for 20 minutes to remove the Fmoc group. The resin was washed to obtain H- _D -Tyr( ^tBu )-D-Trp(Boc)-Asn(Trt)-Thr( ^tBu )-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp( Boc)-Rink Amide MBHA resin. The obtained resin was treated with 188.7 μL (2 mmol) of Ac ₂ O and 348.4 μL (2 mmol) of DIEA in 20 mL of DMF at room temperature for 30 minutes to acetylate the N-terminal. Then the resin was washed and dried to obtain 4.168g of Ac- _D -Tyr( ^t Bu) _-D -Trp(Boc)-Asn(Trt)-Thr( ^t Bu)-Phe-AzaGly-Leu-Arg(Boc ₂ , Me )-Trp(Boc)-Rink Amide MBHA resin.

15 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added to half of the obtained resin, ie 2.111 g, and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This operation was repeated twice for washing. The residue was extracted with aqueous acetic acid solution, and the extract was filtered to remove the resin and lyophilized to obtain a crude peptide powder. The remaining half of the resin was deprotected under the same conditions to obtain a total of about 650 mg of crude peptide powder. For the obtained crude peptide, about 50 mg each time was purified by the following method, that is, using preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm), using the eluent according to A/B: the eluent of 71/29-61/39 ratio: 0.1% TFA-water and eluent B: the acetonitrile containing 0.1% TFA, carry out linear concentration gradient elution (60 minutes) with the flow rate of 15ml/min ). Fractions containing the product were collected and lyophilized to obtain 255.5 mg of a white powder as a purified sample.

All the white powders were dissolved in 200 mL of aqueous acetonitrile solution, and 492 μL of ion exchange resin AG1×8 AcO ^- form obtained by converting commercially available BioRAD AG1×8 Cl ^- form into acetate form according to the usual method was added. The reaction solution was left to stand for 1 hour while manually stirring the reaction solution from time to time. The solution was concentrated to remove acetonitrile as much as possible. The concentrate was filtered through a membrane filter and lyophilized to obtain 225.3 mg of a white powder as the acetate salt.

Mass spectrum (M+H) ⁺ 1298.7 (calculated 1298.6)

HPLC elution time: 15.6min

Elution condition:

Column YMC-AM301 (4.6×100mm)

Eluent: A linear concentration gradient elution of eluent A/B=80/20-30/70 was used. 0.1% TFA-water was used as eluent A, and acetonitrile containing 0.1% TFA (25mins.)

Flow rate: 1.0ml/min

[Example 25]: Preparation of Ac-des(1)-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 562)

After swelling 5.455 g (0.455 mmol/g) of commercial Rink Amide MBHA resin in DMF, the resin was treated with 50 ml of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc groups. After washing the resulting resin with DMF, the resin was treated by treating the resin with 6.319 g (12 mmol) of Fmoc-Trp(Boc)-OH, 1.908 mL (12 mmol) of DIPCDI and 24 mL (12 mmol) of a 0.5 M HOAt/DMF solution at room temperature for 90 Minutes, introduce Trp (Boc), obtain Fmoc-Trp (Boc)-Rink Amide MBHA resin. According to the same method, Orn (Mtt) was introduced to obtain 3 mmol of Fmoc-Orn (Mtt)-Trp (Boc)-Rink Amide MBHA resin. The resulting resin was washed with DCM, and after swelling, 75 mL of TFA/TIS/TFE/DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solvent was evaporated. This operation was repeated until the yellow coloring caused by free Mtt groups in the solution disappeared when TFA/TIS/TFE/DCM (1/5/19/75) solution was added, thus removing the Mtt groups.

The resulting Fmoc-Orn-Trp(Boc)-Rink AmideMBHA resin was neutralized with a 5%-DIEA/DCM solution. After washing with DCM, 40 mL of DCM-TFE (4:1) and 2.919 g (9 mmol) of N-methyl-N,N'-di-Boc-1- amidinopyrazole. DIEA was added to the mixture, the pH of the solution was adjusted to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. In the same manner as above, Fmoc-Leu was introduced into the obtained resin. The Fmoc group was removed from the resulting Fmoc-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin (2 mmol) to give H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin (2 mmol).

Separately, 3.489 g (12 mmol) of Fmoc-NHNH ₂ .HCl were suspended in 30 mL of DMF. Under ice-cooling, a suspension obtained by suspending 1.849 mg (11.4 mmol) of CDI in 20 mL of THF was added to the suspension, and then 4.181 mL (24 mmol) of DIEA was added, followed by stirring at room temperature for 1 hour. The resulting reaction solution was added to the aforementioned H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-RinkAmide MBHA resin, followed by stirring at room temperature for 15 hours. After the reaction, the resin was washed and dried to obtain 8.2496 g of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-RinkAmide MBHA resin.

After swelling 2.646 g (1 mmol) of the resulting resin in DMF, the resin was treated with 30 ml of a 20% piperidine/DMF solution for 20 minutes to remove the Fmoc group. After washing the resin with DMF, the resin was mixed with 1.630 g (4 mmol) of Trt-Phe-OH, 2.086 g (4 mmol) of PyAOP, 8 mL (4 mmol) of 0.5M HOAt/DMF and 2.787 mL (16 mmol) of DIEA at room temperature Treat at low temperature for 90 minutes to obtain Trt-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin Phe. After the resin was washed with DCM and swelled, 30 mL of TFA/TIS/TFE/DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes and the solvent was evaporated. This operation was repeated until the TFA/TIS/TFE/DCM (1/5/19/75) solution was added until the yellow coloration caused by the free Trt groups in the solution disappeared, thus removing the Trt groups. The obtained H-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin was neutralized with 5%-DIEA/DMF solution, and washed with DMF. Afterwards, the 0.5M HOAt/DMF of resin and 1.590g (4mmol) of Fmoc-Thr( ^t Bu)-OH, 0.636mL (4mmol) and 8mL (4mmol) of DIPCDI were treated at room temperature for 90 minutes to introduce Thr( ^t Bu). Then, the operation of de-Fmoc protection by treating with 30 ml of 20% piperidine/DMF solution for 20 minutes and the operation of condensation by the same DIPCDI/HOAt method as introducing Thr( ^tBu ) were carried out to obtain Fmoc-Asn(Trt) -Ser( ^tBu )-Phe-AzaGly-Leu-Arg( _Boc2 ,Me)-Trp(Boc)-Rink AmideMBHA resin. The resulting resin was deFmoc protected. The resin was then mixed with 1.476 g (3.8 mmol) of Fmoc- _D -Pya(4)-OH, 2.086 mg (4 mmol) of PyAOP, 8 mL of 0.5MHOAt/DMF (4 mmol) and 2.439 mL of DIEA (14 mmol) at room temperature After 90 minutes of treatment, _D -Pya (4) was introduced. Then, according to the same DIPCDI/HOAt method as introducing Thr( ^t Bu), _D -Tyr( ^t Bu) was introduced into the resin to obtain Fmoc- _D -Tyr( ^t Bu)-D-Pya(4)-Asn( Trt)-Thr( ^tBu )-Phe-AzaGly-Leu-Arg( _Boc2 , Me)-Trp(Boc)-Rink Amide MBHA resin. The resulting resin was treated with 30 ml of a 20% piperidine/DMF solution for 20 minutes to remove the Fmoc group. The resulting resin was washed to obtain H- _D -yr( ^tBu ) _-D -Pya(4)-Asn(Trt)-Thr( ^tBu )-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp( Boc)-Rink Amide MBHA resin. The obtained resin was treated with 188.7 μL (2 mmol) of Ac ₂ O and 348.4 μL (2 mmol) of DIEA in 20 mL of DMF at room temperature for 30 minutes to acetylate the N-terminal. Afterwards, the resin was washed and dried to obtain 1mmolAc- _D -Tyr( ^tBu ) _-D -Pya(4)-Asn(Trt)-Thr( ^tBu )-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp (Boc)-Rink Amide MBHA resin.

To the obtained resin, 30 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added, and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, and the resulting precipitate was centrifuged to remove the supernatant. This operation was repeated twice for washing. After extracting the residue with an aqueous acetic acid solution, the extract was filtered to remove the resin and lyophilized to obtain 949.0 mg of crude peptide powder. To the obtained crude peptide, about 50 mg each time was purified by the following method, that is, using preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm), at 15 ml/min The flow rate is successively eluted with eluent A/B: 90/10 for 8 minutes, A/B: 75/25 for elution, and it takes 7 minutes to increase the concentration, and the eluent is A/B: 75/25-65 /35 linear concentration gradient elution (60 minutes), wherein eluent A: 0.05% TFA-water, eluent B: acetonitrile containing 0.05% TFA. Fractions containing the product were collected and lyophilized to obtain 361.1 mg of a white powder as a purified sample.

All the resulting white powders were dissolved in 200 mL of aqueous acetonitrile solution, and 1.434 mL of ion exchange resin AG1×8 AcO ^- form, which was obtained by converting the commercially available BioRAD AG1×8Cl ^- form into the acetate form according to the usual method . The reaction solution was left to stand for 1 hour while manually stirring the reaction solution from time to time. The solution was concentrated to remove acetonitrile as much as possible. The concentrate was filtered through a membrane filter and lyophilized to obtain 309.3 mg of a white powder as the acetate salt.

Mass spectrum (M+H) ⁺ 1260.4 (calculated 1260.4)

HPLC elution time: 15.5min

Elution conditions:

Column Wakosil-II 5C18 HG (4.6×100mm)

Eluent: used the linear concentration gradient elution of eluent A/B=100/0-50/50, eluent A: 0.1% TFA-water, eluent B: the acetonitrile ( 25mins.)

Flow rate: 1.0ml/min

[Example 26]: Preparation of Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9]MS10 (Compound No. 571)

After swelling 2.5 g (0.4 mmol/g) of commercial Rink Amide MBHA resin in DMF, the resin was treated with 50 ml of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc groups. After washing the resulting resin with DMF, the resin was treated with 1.550 g (4 mmol) of Fmoc-Phe-OH, 0.636 mL (4 mmol) of DIPCDI and 8 mL (4 mmol) of a 0.5 M HOAt/DMF solution at room temperature for 90 minutes, Phe was introduced to obtain Fmoc-Phe-Rink Amide MBHA resin. According to the same method, Orn (Mtt) was introduced to obtain 1 mmol of Fmoc-Orn (Mtt)-Trp (Boc)-RinkAmide MBHA resin. The obtained resin was washed with DCM, and after swelling, 25 mL of TFA/TIS/TFE/DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solvent was evaporated. This operation was repeated until the yellow coloring caused by free Mtt groups in the solution disappeared when TFA/TIS/TFE/DCM (1/5/19/75) solution was added, thus removing the Mtt groups.

The resulting Fmoc-Orn-Phe-Rink Amide MBHA resin was neutralized with a 5%-DIEA/DCM solution. After washing with DCM, 25 mL of DCM-TFE (4:1) and 0.973 g (3 mmol) of N-methyl-N,N'-di-Boc-1- amidinopyrazole. DIEA was added to the mixture, the pH of the solution was adjusted to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg(Boc ₂ , Me)-Phe-Rink Amide MBHA resin. In the same manner as above, Fmoc-Leu was introduced into the obtained resin. The Fmoc group was removed from the obtained Fmoc-Leu-Arg(Boc ₂ , Me)-Phe-RinkAmide MBHA resin (1 mmol) to obtain H-Leu-Arg(Boc ₂ , Me)-Phe-Rink Amide MBHA resin (1 mmol) .

Separately, 1.163 g (4 mmol) of Fmoc-NHNH ₂ .HCl was suspended in 10 mL of DMF. Under ice-cooling, a suspension obtained by suspending 0.568 mg (3.5 mmol) of CDI in 10 mL of THF was added to the suspension, and then 1.307 mL (7.5 mmol) of DIEA was added, followed by stirring at room temperature for 1 hour . The resulting reaction solution was added to the aforementioned H-Leu-Arg(Boc ₂ , Me)-Phe-RinkAmide MBHA resin, followed by stirring at room temperature for 15 hours. After the reaction, the resin was washed and dried to obtain 3.134 g of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Phe-Rink AmideMBHA resin.

According to the same method as in Example 24, use the above resin to condense with Trt-Phe-OH 0.5AcOEt to obtain 1.94g Trt-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink AmideMBHA resin , and the resulting resin was washed with DCM. After swelling, 12 mL of TFA/TIS/TFE/DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solvent was evaporated. This operation was repeated until the TFA/TIS/TFE/DCM (1/5/19/75) solution was added until the brown-yellow coloring caused by the free Trt groups in the solution disappeared, thus removing the Trt groups. By washing the resin, 1.66 g of H-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Phe-Rink Amide MBHA resin was obtained. Using 553 mg of the obtained resin, the peptide chain was extended using the peptide synthesizer ABI-433A (Fmoc/DCC/HOBt) to obtain HD-Tyr(But)-D-Trp(Boc)-Asn(Trt)-Thr(But)-Phe- AzaGly-Leu-Arg (Boc2, Me)-Phe-Rink Amide MBHA resin. To this product was added 5 mL of DMF, 111 mg of AcONB and 44 ml of DIEA, and the resin was shaken for 2 hours. The resin was dried after washing to obtain 0.78 g of Ac-D-Tyr(But)-D-Trp(Boc)-Asn(Trt)-Thr(But)-Phe-AzaGly-Leu-Arg(Boc2, Me)-Phe-Rink Amide MBHA resin. 6 mLd of TFA/thioanisole/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added to the resin, and the resin was shaken for 2 hours. After removing the resin by filtration, the solvent was distilled off. By adding diethyl ether, a precipitate was obtained. After centrifugation, the supernatant was removed, the washing was repeated twice, and the residue was extracted with acetate solution. After removing the resin by filtration, use a preparative HPLC using a YMC Pack R&D-ODS-5-B S-5, 120A column (30×250mm), and use an eluent A/B: 71/29-61/39 ratio Eluent A: 0.1% TFA-water and Eluent B: acetonitrile containing 0.1% TFA, linear concentration gradient elution was performed at a flow rate of 15 ml/min (60 minutes). Fractions containing the product were collected and lyophilized to obtain a white powder as a purified sample. The purified sample was lyophilized. The crude peptide obtained by using 553 mg of H-Phe-AzaGly-Leu-Arg(Boc2, Me)-Phe-Rink Amide MBHA resin in the same manner was purified by preparative HPLC to obtain a total of 237.6 mg of white powder as a purified sample.

236.1 mg of the obtained white powder was dissolved in 200 mL of aqueous acetonitrile solution, and 935 μL of ion exchange resin AG1×8 AcO ^- form was added to the solution, which converted the commercially available BioRAD AG1×8 Cl ^- form into acetic acid according to the usual method From the salt type. The reaction solution was left to stand for 1 hour while manually stirring the reaction solution from time to time. The solution was concentrated to remove acetonitrile as much as possible. The concentrate was filtered through a membrane filter and lyophilized to obtain 204.6 mg of a white powder as the acetate salt.

Mass spectrum (M+H) ⁺ 1259.5 (calculated 1259.6)

HPLC elution time: 13.2min

Elution condition:

Column YMC-AM301 (4.6×100mm)

Eluent: used the linear concentration gradient elution of eluent A/B=80/20-30/70, eluent A: 0.1% TFA-water, eluent B: the acetonitrile ( 25mins.)

Flow rate: 1.0ml/min

[Example 27]: Preparation of Ac-des(1)-[D-Tyr2, D-Trp3, Alb4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 579)

After swelling 5 g (0.4 mmol/g) of commercial Rink Amide MBHA resin in DMF, the resin was treated with 50 ml of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc groups. After washing the resulting resin with DMF, the resin was treated at room temperature by treating the resin with 4.213 g (8 mmol) of Fmoc-Trp(Boc)-OH, 1.272 mL (8 mmol) of DIPCDI, and 16 mL (8 mmol) of a 0.5 M HOAt/DMF solution In 90 minutes, Trp(Boc) was introduced to obtain Fmoc-Trp(Boc)-Rink AmideMBHA resin. According to the same method, Orn (Mtt) was introduced to obtain 2 mmol of Fmoc-Orn (Mtt)-Trp (Boc)-Rink Amide MBHA resin. Wash the obtained resin with DCM, after swelling, add 50mL TFA/TIS/TFE/DCM (1/5/19/75), shake the mixture for 10 minutes, evaporate the solvent. This operation was repeated until the yellow coloring caused by free Mtt groups in the solution disappeared when TFA/TIS/TFE/DCM (1/5/19/75) solution was added, thus removing the Mtt groups.

The resulting Fmoc-Orn-Trp(Boc)-Rink AmideMBHA resin was neutralized with a 5%-DIEA/DCM solution. After washing with DCM, 25 mL of DCM-TFE (4:1) and 1.946 g (6 mmol) of N-methyl-N,N'-di-Boc-1- amidinopyrazole. DIEA was added to the mixture, the pH of the solution was adjusted to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. In the same manner as above, Fmoc-Leu was introduced into the obtained resin. The Fmoc group was removed from the resulting Fmoc-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin (2 mmol) to give H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)- Rink Amide MBHA resin (2 mmol).

Separately, 2.326 g (8 mmol) of Fmoc-NHNH ₂ .HCl was suspended in 20 mL of DMF. Under ice-cooling, a suspension obtained by suspending 1.297 mg (8 mmol) of CDI in 20 mL of THF was added to the suspension, and then 2.787 mL (16 mmol) of DIEA was added, followed by stirring at room temperature for 1 hour . The resulting reaction solution was added to the aforementioned H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-RinkAmide MBHA resin, followed by stirring at room temperature for 15 hours. After the reaction, the resin was washed and dried to obtain 2 mmol of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-RinkAmide MBHA resin.

Using 868 mg (0.257 mmol) of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin, using ABI 433A, repeated condensation by DCC/HOBt method, introducing Thr( ^t Bu), Alb, _D -Trp(Boc) and _D -Tyr( ^t Bu) to get H- _D -Tyr( ^t Bu) _-D -Trp(Boc)-Alb-Ser( ^t Bu)-Phe-AzaGly-Leu-Arg (Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. The N-terminus of the resulting resin was acetylated by treatment with 111 mg (0.5 mmol) of AcONB and 87 μL (0.5 mmol) of DIEA in 5 mL of DMF at room temperature for 10 hours. Afterwards, the resin was washed and dried to obtain Ac- _D -Tyr( ^t Bu) _-D -Trp(Boc)-A1b-Ser( ^t Bu)-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc ) - Rink Amide MBHA resin.

To the resulting resin, 6 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5) was added, and the suspension was shaken for 2 hours. After removing the resin by filtration, the solvent was distilled off. Precipitation was obtained by adding diethyl ether. After centrifugation, washing by removing the supernatant was repeated twice, and the residue was extracted with acetate solution. After removal of the resin by filtration, the fractions were purified using preparative HPLC using a YMC Pack R&D-ODS-5-B S-5, 120A column (30 x 250 mm) with eluents A/B according to: Eluent A: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA in a ratio of 69/31-59/41 were eluted with a linear concentration gradient at a flow rate of 15 ml/min (60 minutes). Fractions containing the product were collected and lyophilized to obtain 106.5 mg of white powder as a purified sample.

All the resulting white powders were dissolved in 100 mL of aqueous acetonitrile solution, and 400 μL of ion exchange resin AG1×8 AcO ^- form, which was obtained by converting commercially available BioRAD AG1×8 Cl ^- form into acetate form according to the usual method, was added. The reaction solution was left to stand for 1 hour while manually stirring the reaction solution from time to time. The solution was concentrated to remove acetonitrile as much as possible. The concentrate was filtered through a membrane filter and lyophilized to give 97.5 mg of a white powder as the acetate salt.

Mass spectrum (M+H) ⁺ 1299.5 (calculated 1299.6)

HPLC elution time: 19.0min

Elution conditions:

Column Wakosil-II (4.6×100mm)

Eluent: Eluent A/B = 100/0-50/50 linear concentration gradient elution (25mins.), eluent A: 0.1% TFA-water, eluent B: containing 0.1% Acetonitrile in TFA

Flow rate: 1.0ml/min

[Example 28]

(Synthetic Method X): Preparation of Ac-des(1)-[D-Tyr2, D-Trp3, Dap(For)4, AzaGly7, Arg(Me)9, Trp10]MS10 (Compound No. 585)

After swelling 5 g (0.4 mmol/g) of commercial Rink Amide MBHA resin in DMF, the resin was treated with 50 ml of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc groups. After washing the resulting resin with DMF, the resin was treated by treating the resin with 4.213 g (8 mmol) of Fmoc-Trp(Boc)-OH, 1.272 mL (8 mmol) of DIPCDI and 16 mL (8 mmol) of 0.5M HOAt/DMF at room temperature for 90 Minutes, introduce Trp (Boc), obtain Fmoc-Trp (Boc)-Rink Amide MBHA resin. According to the same method, Orn (Mtt) was introduced to obtain 2 mmol of Fmoc-Orn (Mtt)-Trp (Boc)-Rink Amide MBHA resin. Wash the obtained resin with DCM, after swelling, add 50mL TFA/TIS/TFE/DCM (1/5/19/75), shake the mixture for 10 minutes, and evaporate the solvent. This operation was repeated until the yellow coloring caused by free Mtt groups in the solution disappeared when TFA/TIS/TFE/DCM (1/5/19/75) solution was added, thus removing the Mtt groups.

The resulting Fmoc-Orn-Trp(Boc)-Rink AmideMBHA resin was neutralized with a 5%-DIEA/DCM solution. After washing with DCM, 25 mL of DCM-TFE (4:1) and 1.946 g (6 mmol) of N-methyl-N,N'-di-Boc-1 obtained in Reference Example 1 were added to the resin - amidinopyrazole. DIEA was added to the mixture, the pH of the solution was adjusted to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin. Following the same method as above, Fmoc-Leu was introduced into the resin obtained by the same method as above. The Fmoc group was removed from the resulting Fmoc-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin (2 mmol) to give H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)- Rink Amide MBHA resin (2 mmol).

Separately, 2.326 g (8 mmol) of Fmoc-NHNH ₂ .HCl was suspended in 20 mL of DMF. Under ice-cooling, a suspension obtained by suspending 1.297 mg (8 mmol) of CDI in 20 mL of THF was added to the suspension, and then 2.787 mL (16 mmol) of DIEA was added, followed by stirring at room temperature for 1 hour. The resulting reaction solution was added to the above-mentioned H-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink AmideMBHA resin, followed by stirring at room temperature for 15 hours. After the reaction, the resin was washed and dried to obtain 2 mmol of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink AmideMBHA resin.

Using 868 mg (0.257 mmol) of Fmoc-AzaGly-Leu-Arg(Boc ₂ , Me)-Trp(Boc)-Rink Amide MBHA resin, using ABI 433A, repeated condensation by DCC/HOBt method, introducing Thr( ^t Bu), Dap(Mtt), _D -Trp(Boc) and _D -Tyr( ^t Bu), get H- _D -Tyr( ^t Bu) _-D -Trp(Boc)-Dap(Mtt)-Ser( ^t Bu)-Phe - AzaGly-Leu-Arg( _Boc2 ,Me)-Trp(Boc)-Rink Amide MBHA resin. The N-terminus of the resulting resin was acetylated by treatment with 111 mg (0.5 mmol) of AcONB and 87 μL (0.5 mmol) of DIEA in 5 mL of DMF at room temperature for 4 hours. Afterwards, the resin was washed and dried to obtain Ac- _D -Tyr( ^t Bu)- _D -Trp(Boc)-Dap(Mtt)-Ser( ^t Bu)-Phe-AzaGly-Leu-Arg(Boc ₂ , Me)- Trp(Boc)-Rink Amide MBHA resin.

To the resulting resin was added 6 mL of TFA/PhSMe/m-cresol/H ₂ O/TIS/EDT (80/5/5/5/2.5/2.5), and the suspension was shaken for 2 hours. After removing the resin by filtration, the solvent was distilled off. Precipitation was obtained by adding diethyl ether. After centrifugation, the supernatant was removed, washed twice and the residue was extracted with acetate. After removing the resin by filtration, the fractions were purified by using a preparative HPLC using a YMC Pack R&D-ODS-5-B S-5, 120A column (30×250 mm) according to eluent A/B: 71 Eluent A: 0.1% TFA-water and eluent B: acetonitrile containing 0.1% TFA in the ratio of /29-61/39, and the linear concentration gradient elution was performed at a flow rate of 15 ml/min (60 minutes). Fractions containing the product were collected and lyophilized to obtain 106.5 mg of white powder as a purified sample.

All the resulting white powders were dissolved in 100 mL of aqueous acetonitrile solution, and 400 μL of ion exchange resin AG1×8 AcO ^- form, which was obtained by converting commercially available BioRAD AG1×8 Cl ^- form into acetate form according to the usual method, was added. The reaction solution was left to stand for 1 hour while manually stirring the reaction solution from time to time. The solution was concentrated to remove acetonitrile as much as possible. The concentrate was filtered through a membrane filter and lyophilized to obtain 58.3 mg of a white powder as the acetate salt.

Mass spectrum (M+H) ⁺ 1284.7 (calculated 1284.6)

HPLC elution time: 17.9min

Elution condition:

Column Wakosil-II (4.6×100mm)

Eluent: used the linear concentration gradient elution of eluent A/B=100/0-50/50, eluent A: 0.1% TFA-water, eluent B: the acetonitrile ( 25mins.)

Flow rate: 1.0ml/min

The structures of the compounds synthesized as in Examples 1 to 24 and the physicochemical properties of these compounds are shown in Tables 1 to 11 below.

[Table 1]

Compound number M+H+(obs.) M+H-(cal.)  HPLC(min.) HPLC mode resolve resolution 1 Transferin 5858.4 5858.5 18.1 d M 2 Lys-Asp-Leu-Pro-Asn-MS10 1869.6 1869.9 18.6 d M 3 MS10 1302.5 1302.6 18.7 d M 4 des(1)-MS10 1139.6 1139.6 18.1 d M 17 [Pya(4)10]MS10 1303.6 1303.6 14.7 d M 18 [Tyr(Me)10]MS10 1332.7 1332.7 17.7 d M 19 [Phe(2F)10]MS10 1320.5 1320.6 17.8 d M twenty three [Tyr5] MS10 1378.6 1378.8 18.6 d M twenty four [Leu5] MS10 1328.7 1328.7 19.8 d M 30 Acetyl-MS10 1344.5 1344.6 29.2 b A 31 Fmoc-MS10 1524.6 1524.7 23.1 b A 38 [D-Ser5] MS10 1302.5 1302.6 11.8 c A 39 [D-Asn4] MS10 1302.5 1302.6 11.6 c A 40 [D-Trp3] MS10 1302.5 1302.6 11.5 c A 41 [D-Asn2] MS10 1302.5 1302.6 11.7 c A 42 [D-Tyr1] MS10 1302.5 1302.6 11.4 c A 44 [Lys9] MS10 1274.6 1274.6 11.7 c A 45 [Ala8] MS10 1260.5 1260.6 10.0 c A 50 [Ala7] MS10 1316.3 1316.7 12.2 c A 51 [NMePhe10] MS10 1316.3 1316.7 22.7 a A 53 des(1-3)-Fmoc-MS10 1061.2 1061.5 27.3 a A 54 des(1-2)-Fmoc-MS10 1247.4 1247.6 29.6 a A 55 des(1)-Fmoc-MS10 1361.6 1361.6 28.2 a A 56 [Lys2] MS10 1316.6 1316.7 16.8 d M 57 [Asp2]MS10 1303.7 1303.6 17.7 d M 58 [Tyr2] MS10 1351.7 1351.7 18.2 d M 59 [Leu2] MS10 1301.6 1301.7 19.2 d M 60 [Pya(3)10]MS10 1303.6 1301.6 14.7 d M 61 [Phe(4F)10]MS10 1320.6 1320.6 18.0 d M 67 [Ala3] MS10 1187.4 1187.6 9.3 c A 68 [Leu3] MS10 1229.6 1229.6 11.1 c A 69 [Ser3] MS10 1203.5 1203.6 8.9 c A 70 [Asp3]MS10 1231.6 1231.6 8.0 c A 71 [Lys3] MS10 1244.6 1244.7 8.1 c A 72 [Ala1] MS10 1210.5 1210.6 11.1 c A 73 [Lou1] MS10 1252.6 1252.7 12.5 c A 74 [Ser1] MS10 1226.6 1226.6 10.9 c A 75 [Asp1] MS10 1254.4 1254.6 11.0 c A

[Table 2]

76 [Lys1] MS10 1267.6 1267.7 10 c A 77 [Phe(4CN)10]MS10 1327.5 1327.6 17.2 d m 78 [Trp (For) 3, Phe (4CN) 10] MS10 1355.6 1355.6 17.4 d m 79 [Hph10] MS10 1316.5 1316.7 20.6 a A 81 [NMeArg9]MS10 1316.3 1316.7 23.3 a A 82 [Arg(Me)9]MS10 1316.5 1316.7 20.1 a E 83 [Arg(Me2)asy9]MS10 1330.4 1330.7 21.3 a A 87 des(4-5)-Boc-MS10 1201.6 1201.6 22.5 d m 88 des(4-5)-MS10 1101.5 1101.5 18.6 d m 90 [Lys9, 9ψ10, CH2NH] MS10 1260.6 1260.7 19.8 a D 91 [8ψ9,CH2NH]MS10 1288.7 1288.7 20.5 a D 97 [Har9] MS10 1316.3 1316.7 11.9 c A 98 [Lys(Me2)9]MS10 1302.6 1302.7 11.8 c A 101 [Ser7] MS10 1332.6 1332.6 11.6 c A 105 [Nle8] MS10 1302.3 1302.6 11.9 c A 107 [Val8]MS10 1288.5 1288.6 11 c A 109 [Tyr10] MS10 1408.4 1408.7 10.2 c A 110 [Nal(2)10]MS10 1332.4 1332.6 13.5 c A 111 [Phe(F5)10]MS10 1392.2 1392.6 13.5 c A 112 [Cha10] MS10 1308.4 1308.7 13.4 c A 114 des(1-3)-3-(3-indolyl)propionyl-MS10 1010.5 1010.5 13.8 c A+1 121 des(1-4)-[Trp5]MS10 824.3 824.5 22.5 d m 123 [NMeLeu8] MS10 1316.7 1316.7 12.7 c A 126 [NMeSer5] MS10 1317 1316.7 11.8 c A 127 [D-Asn4, NMePhe6] MS10 1316.7 1316.7 11.8 c A 128 [10ψ,CSNH]MS10 1318.4 1318.6 21.8 a C 129 [Arg(Me2)sy9]MS10 1331.2 1330.7 20.9 a A 130 [Phe(4Cl)10]MS10 1336.4 1336.6 13.1 c A 131 [Phe(4NH2)10]MS10 1317.4 1317.6 8.3 c A 132 [Phe(4NO2)10]MS10 1347.4 1347.6 12.2 c A 133 [Nal(1)10]MS10   1352.6 1352.7 13.5 c A 134 [Trp10] MS10 1341.5 1341.6 12 c A 137 [Nle9] MS10 1259.4 1259.6 15.3 c A

138 [Cit9] MS10 1303.4 1303.6 12.2 c A 140 [Arg(Me)9, NMePhe10] MS10 1330.4 1330.7 twenty one a E 141 [D-Tyr1, Arg(Me)9]MS10 1316.9 1316.7 20.2 a E 142 [D-Tyr1, D-Trp3, Arg(Me)9] MS10 1316.7 1316.7 20.1 a E 143 [D-Trp3, Arg(Me)9]MS10 1316.7 1316.7 20.3 a E 144 des(1-3)-Fmoc-[Arg(Me)9]MS10 1075.2 1075.5 26 a E 145 des(1-2)-Fmoc-[Arg(Me)9]MS10 1261.2 1261.6 28.6 a E

[table 3]

146 [10ψ, CSNH, D-Tyr1] MS10 1318.4 1318.6 21.4 a C 150 [Tyr6] MS10 1318.4 1318.6 10.2 c A 151 [Nal(1)6]MS10   1352.6 1352.7 13.5 c A 152 [Nal(2)6]MS10   1352.6 1352.7 13.5 c A 153 [Phe(F5)6]MS10 1392.5 1392.6 13.7 c A 154 [Phe(4F)6]MS10 1320.8 1320.6 12.3 c A 156 [Cha6] MS10 1308.2 1308.5 13.2 c A 163 [6ψ7,CH2NH]MS10 1288.7 1288.7 18.2 a D 165 [Dap(Gly)9]MS10 1289.8 1289.6 19.2 a E 166 [8ψ7,CSNH]MS10 1318.7 1318.6 20.8 a F 169 [D-Tyr1, Ala3, Arg(Me)9] MS10 1202.1 1201.6 9.0 c E 170 [D-Tyr1, Ser3, Arg(Me)9] MS10 1218.2 1217.6 8.8 c E 171 [D-Tyr1, Cha3, Arg(Me)9] MS10 1284.2 1283.7 12.1 c E 172 [D-Tyr1, Cha6, Arg(Me)9] MS10 1402.9 1322.7 13.1 c E 173 [D-Tyr1, Ala7, Arg(Me)9] MS10 1410.9 1330.7 12.2 c E 174 [D-Tyr1, Arg(Me)9, Trp10] MS10 1335.3 1335.7 11.7 c E 176 [AzaGly7] MS10 1303.3 1303.6 18.9 a G 181 [D-Tyr1, Cha3, 6, Arg(Me)9] MS10 1370.6 1370.6 13.9 c E 182 [D-Tyr1, Cha3, 6, Arg(Me)9, Trp10] MS10 1328.2 1328.7 21.3 a E 183 [Phe(4NH2)9]MS10 1328.2 1308.6 19.4 a A 184 [Phe(4-guanidino)9]MS10 1350.4 1350.6 19.7 a E 185 [Dap(GnGly)9]MS10 1331.2 1331.6 19.1 a E 186 [Trp(For)10]MS10 1369.3 1369.6 18.6 a B 187 [Abu8] MS10 1274.4 1274.6 10.4 c A 189 [Ala(3-Bzt)10]MS10 1358.4 1358.6 13.4 c A 190 [D-Tyr1, Cha3, AzaGly7, Arg(Me)9] MS10 1284.5 1284.7 19.3 a H 191 [D-Tyr1, Ser3, AzaGly7, Arg(Me)9] MS10 1218.4 1218.6 15.9 a H 192 [D-Tyr1, Arg(Et)9]MS10 1330.5 1330.7 18.9 a E 193 [D-Tyr1, Arg(n-Pr)9] MS10 1344.8 1344.7 19.4 a E 194 [D-Tyr1, Arg(Ac)9]MS10 1345.1 1344.6 18.8 a E 197 [Phe(3F)10]MS10 1320.6 1320.6 12.2 c A 198 [Phe(3,4F2)10]MS10 1338.7 1338.6 12.7 c A 199 [Phe(3,4C12)10]MS10 1370.6 1370.6 13.1 c A 200 [Phe(3CF3)10]MS10 1370.6 1370.6 13.1 c A 201 [Ala(2-Qui)10]MS10 1353.4 1353.6 9.8 c A 203 [D-Tyr1, Cha6, Arg(Me)9] MS10 1322.4 1322.7 12.9 c E 204 [D-Tyr1, Ala7, Arg(Me)9] MS10 1330.4 1330.7 11.7 c E 205 [D-Tyr1, Thr3, Arg(Me)9] MS10 1231.4 1231.6 9.0 c E 206 [D-Tyr1, Ile3, Arg(Me)9] MS10 1243.6 1243.7 10.1 c E 207 [D-Tyr1, Ser4, Arg(Me)9] MS10 1289.5 1289.6 11.7 c E

[Table 4]

208 [D-Tyr1, Thr4, Arg(Me)9] MS10 1303.4 1303.7 12.0 c E 209 [D-Tyr1, Gln4, Arg(Me)9] MS10 1330.8 1330.7 11.6 c E 210 [D-Tyr1, Ala4, Arg(Me)9] MS10 1273.7 1273.6 12.3 c E 211 [D-Tyr1, Thr5, Arg(Me)9] MS10 1330.7 1330.7 11.7 c E 212 [D-Tyr1, Ala5, Arg(Me)9] MS10 1300.5 1300.7 12.1 c E 213 [D-Tyr1, Val8, Arg(Me)9] MS10 1302.5 1302.6 10.4 c E 214 [D-Tyr1, Gln2, Arg(Me)9] MS10 1330.5 1330.7 11.4 c E 215 [D-Tyr1, Thr2, Arg(Me)9] MS10 1303.4 1303.7 11.9 c E 216 des(1)-[D-Asn2, Arg(Me)9]MS10 1153.3 1153.6 11.1 c E 217 des(1)-[D-Tyr2, Arg(Me)9]MS10 1202.4 1202.6 12.3 c E 218 [N((CH2)3Gn))Gly9]MS10 1302.5 1302.7 18.6 a L 220 [Arg(Et)9]MS10 1330.7 1330.7 19.5 a E 221 [D-Tyr1, Thr3, AzaGly7, Arg(Me)9] MS10 1232.5 1232.6 16.1 a H 222 des(1)-[D-Tyr2, AzaGly7, Arg(Me)9] MS10 1203.5 1203.6 19.3 a H 223 des(1-2)-[D-Trp3, Arg(Me)9]MS10 1039.5 1039.5 11.0 c E 224 des(1)-[D-Tyr2, D-Trp3, Arg(Me)9] MS10 1202.4 1202.6 12.2 c E 225 des(1)-[D-Asn2, D-Trp3, Arg(Me)9] MS10 1153.6 1153.6 11.1 c E 228 des(1)-[D-Tyr2, Ser3, Arg(Me)9] MS10 1103.5 1103.6 9.5 c E 227 des(1)-[D-Tyr2,Thr3,Arg(Me)9]MS10 1117.3 1117.6 9.8 c E 228 des(1)-[D-Tyr2, Ile3, Arg(Me)9] MS10 1129.6 1129.6 11.5 c E 229 [D-Tyr1, Val3, Arg(Me)9] MS10 1229.5 1229.6 9.7 c E 230 [D-Tyr1, D-Asn2, Arg(Me)9] MS10 1316.5 1316.7 11.8 c E 231 [D-Tyr1, D-Asn2, D-Trp3, Arg(Me)9] MS10 1316.3 1316.7 11.7 c E 232 [D-Tyr1, AzaGly7, Arg(Me)9] MS10 1317.0 1317.6 21.0 a H 233 [D-Tyr1, Ile3, AzaGly7, Arg(Me)9] MS10 1244.1 1244.7 20.9 a H 234 [D-Tyr1, Val3, AzaGly7, Arg(Me)9] MS10 1230.5 1230.6 20.6 a H 235 [D-Tyr1, Ala3, AzaGly7, Arg(Me)9] MS10 1202.5 1202.6 20.5 a H 236 [D-Tyr1, D-Trp3, AzaGly7, Arg(Me)9] MS10 1317.6 1317.6 20.9 a H 237 [D-Tyr1, D-Asn2, AzaGly7, Arg(Me)9] MS10 1317.6 1317.6 20.9 a H 238 [D-Tyr1, D-Asn2, D-Trp3, AzaGly7, Arg(Me)9] MS10 1317.6 1317.6 20.6 a h 239 des(1)-[D-Tyr2, Ser3, AzaGly7, Arg(Me)9] MS10 1104.1 1104.6 19.0 a h 240 des(1)-[D-Tyr2, Ile3, AzaGly7, Arg(Me)9] MS10 1130.1 1130.6 20.3 a h 241 des(1)-[D-Tyr2, Thr3, AzaGly7, Arg(Me)9] MS10 1188.0 1118.6 20.3 a h 242 des(1)-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9] MS10 1202.9 1203.6 21.2 a h 244 [D-Tyr1, Phe3, AzaGly7, Arg(Me)9] MS10 1278.6 1278.6 10.5 c H 245 [D-Tyr1, Nal(1)3, AzaGly7, Arg(Me)9] MS10 1328.5 1328.7 12.3 c H 246 [D-Tyr1, Nal(2)3, AzaGly7, Arg(Me)9] MS10 1328.7 1328.7 12.3 c H 247 [D-Tyr1, Phe(2Cl)3, AzaGly7, Arg(Me)9] MS10 1315.6 1312.6 11.3 c H

[table 5]

248 [D-Tyr1, Phe(3Cl)3, AzaGly7, Arg(Me)9] MS10 1312.5 1312.6 11.6 c H 249 [D-Tyr1, Phe(4Cl)3, AzaGly7, Arg(Me)9] MS10 1312.5 1312.6 11.7 c H 250 [D-Tyr1, Phe(4NH2)3, AzaGly7, Arg(Me)9] MS10 1293.4 1293.6 7.8 c h 251 [D-Tyr1, Pya(3)3, AzeGly7, Arg(Me)9] MS10 1279.4 1279.6 7.8 c H 252 [D-Tyr1, D-Ala3, AzaGly7, Arg(Me)9] MS10 1202.4 1202.6 8.5 c H 253 [D-Tyr1, Pro3, AzaGly7, Arg(Me)9] MS10 1228.4 1228.6 8.6 c H 254 des(1)-[D-Tyr2, Phe3.AzaGly7, Arg(Me)9] MS10 1164.4 1164.6 11.8 c H 255 des(1)-[D-Tyr2, Nal(2)3, AzaGly7, Arg(Me)9] MS10 1214.5 1214.6 13.7 c H 256 des(1)-[D-Pya(3)2, Phe3, AzaGly7, Arg(Me)9] MS10 1149.3 1149.6 9.5 c H 257 [D-Tyr1, D-Asn2, Phe3, AzaGly7, Arg(Me)9] MS10 1278.5 1278.6 10.9 c H 258 [D-Pya(3)1, AzaGly7, Arg(Me)9] MS10 1302.3 1302.6 10.1 c H 259 [D-Ale1, AzaGly7, Arg(Me)9] MS10 1225.5 1225.6 10.7 c H 260 des(1-3)-3-(3-indolyl)propionyl-[AzaGly7, Arg(Me)9]MS10 1025.2 1025.5 13.7 c I 261 [7ψ8,CH2NH]MS10 1288.1 1288.7 17.2 a D 265 des(1-3)-indole-3-carbonyl-[AzaGly7, Arg(Me)9]MS10 997.3 997.5 12.6 c I 266 des(1-3)-indole-3-acetyl-[AzaGly7, Arg(Me)9]MS10 1011.3 1011.5 12.7 c I 267 des(1-3)-4-(3-indolyl)butanoyl-[AzaGly7, Arg(Me)9]MS10 1039.3 1039.5 14.4 c I 268 des(1-3)-Diphenylacetyl-[AzaGly7, Arg(Me)9]MS10 1048.5 1048.5 15.7 c I 269 des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9]MS10 996.7 986.5 13.5 c I 270 Endo-Phe5a-[D-Tyr1, Phe3, AzaGly7, Arg(Me)9] MS10 1425.5 1425.7 13.4 c h 271 des(1-2)-[AzaGly7, Arg(Me)9]MS10 1040.2 1040.5 10.4 c H 272 des(1-2)-acetyl-[AzaGly7, Arg(Me)9]MS10 1082.3 1082.6 12.8 c H 273 des(1-2)-Amidino-[AzaGly7, Arg(Me)9]MS10 1082.3 1082.6 11.4 c J 274 des(1-2)-acetyl-[Ala3, AzaGly7, Arg(Me)9] MS10 967.3 967.5 9.6 c H 275 des(1-2)-acetyl-[Arg3, AzaGly7, Arg(Me)9] MS10 1052.2 1052.6 8.5 c H 276 des(1-2)-acetyl-[Thr3, AzaGly7, Arg(Me)9] MS10 997.2 997.5 9.4 c H 277 des(1-3)-n-hexanoyl-[AzaGly7, Arg(Me)9]MS10 952.2 952.5 13.4 c I 278 des(1-3)-Cyclohexanecarbonyl-[AzaGly7, Arg(Me)9]MS10 964.3 964.5 13.2 c I 279 des(1-3)-2-(indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9]MS10 1040.2 1040.5 20.1 a N 281 [D-Tyr1, Pya(2)6, Arg(Me)9] MS10 1317.3 1317.6 7.8 c E 282 [D-Tyr1, Pya(4)6, Arg(Me)9] MS10 1317.2 1317.6 8.0 c E

[Table 6]

283 [D-Tyr1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10 1284.3 1284.7 12.3 c h 284 [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg(Me)9] MS10 1232.2 1232.6 8.6 c H 285 [D-Tyr1, Pya(2)3, AzaGly7, Arg(Me)9] MS10 1279.2 1279.6 7.9 c H 286 [D-Tyr1, Pya(4)3, AzaGly7, Arg(Me)9] MS10 1279.2 1279.6 7.7 c H 287 [D-Tyr1, D-Ser2, AzaGly7, Arg(Me)9] MS10 1290.1 1290.6 11.4 c H 288 [D-Tyr1, D-His2, AzaGly7, Arg(Me)9] MS10 1340.2 1340.7 10.3 c H 289 des(1)-[D-Pya(3)2, AzaGly7, Arg(Me)9] MS10 1188.2 1188.6 10.0 c h 290 [D-Pya(3)1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10 1269.5 1269.7 10.9 c H 291 [D-Pya(3)1, D-Tyr2, Cha3, AzaGly7, Arg(Me)9] MS10 1317.4 1318.7 12.0 c H 293 [4ψ5,CH2NH]MS10 1288.1 1288.7 18.4 a D 294 [1ψ2,CH2NH]MS10 1288.4 1288.7 19.2 a D 295 [2ψ3,CH2NH]MS10 1288.1 1288.7 18.2 a D 296 [6ψ7, CSNH, D-Tyr1, Arg(Me)9] MS10 1332.1 1332.6 20.5 a F 297 [D-Tyr1, Thr5, AzaGly7, Arg(Me)9] MS10 1331.2 1330.7 11.3 c H 298 [D-Tyr1, D-Asn2, Thr5, AzaGly7, Arg(Me)9] MS10 1331.1 1330.7 11.6 c H 299 [1ψ2, CH2NH, AzaGly7, Arg(Me)9] MS10 1303.4 1330.7 11.3 c D+H 300 [1ψ2, CH2NH, D-Trp3, AzaGly7, Arg(Me)9] MS10 1303.4 1303.7 10.8 c D+H 301 [D-Tyr1, Ala(2-Qui)3, AzaGly7, Arg(Me)9] MS10 1329.4 1329.6 9.0 c H 302 [D-Tyr1, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10 1279.4 1279.6 7.6 c h 303 [D-Tyr1, D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9] MS10 1279.4 1279.6 7.8 c H 304 [D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9] MS10 1279.4 1279.6 7.7 c H 305 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10 1165.4 1165.6 8.0 c h 306 [D-Pya(4)1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10 1269.5 1269.5 10.8 c h 307 [7ψ8, CH2NH, D-Tyr1, Arg(Me)9] MS10 1302.2 1302.7 17.9 a D+E 308 [6ψ7, CH2NH, D-Tyr1, Arg(Me)9] MS10 1302.3 1302.7 18.1 a D+E 310 [Nar9] MS10 1288.8 1288.6 19.4 a E 311 [Nar(Me)9]MS10 1302.3 1302.6 19.5 a E 312 [Har(Me)9]MS10 1330.2 1330.7 19.5 a E 313 [Dab9] MS10 1246.1 1246.6 19.3 a A 314 [Orn9] MS10 1260.2 1260.6 19.3 a A 315 des(1)-[D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10 1121.3 1121.6 11.4 c h 316 [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg(Me)9, Phe(4F)10] MS10 1250.5 1250.6 17.0 a h 317 [D-Tyr1, D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9, Phe(4F)10] MS10 1297.4 1297.6 16.4 a h 318 [D-Tyr1, AzaGly7, Arg(Me)9, Phe(4F)10] MS10 1335.4 1335.6 19.0 a h

[Table 7]

319 [6ψ7, NHCO, D-Tyr1, Arg(Me)9] MS10 1316.3 1316.7 18.7 a K 322 des(1-3)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9]MS10 987.4 987.5 8.1 c I 323 des(1-3)-4-imidazoleacetyl-[AzaGly7, Arg(Me)9]MS10 962.5 962.5 7.9 c I 324 des(1-3)-4-piperidinecarbonyl-[AzaGly7, Arg(Me)9]MS10 965.5 965.5 7.7 c I 325 des(1-3)-1-piperidineacetyl-[AzaGly7, Arg(Me)9]MS10 979.5 979.5 8.5 c I 326 des(1-3)-1-methylpiperidino-1-acetyl-[AzaGly7, Arg(Me)9]MS10 993.4 993.6 8.7 c I 327 des(1-3)-1-pyridinoacetyl-[AzaGly7, Arg(Me)9]MS10 973.4 973.5 8.1 c I 328 des(1-3)-D-Glucrony1-[AzaGly7, Arg(Me)9]MS10 1030.2 1030.5 7.5 c I 332 des(1-5)-GuAmb-[AzaGly7, Arg(Me)9] MS10 828.6 828.5 9.9 c H+J 333 des(1-5)-GuAmb-[Arg(Me)9]MS10 827.6 827.5 10.6 c E+J 334 des(1-5)-GuAmb-[AzaGly7, Arg(Me)9, Trp10] MS10 867.6 867.5 10.3 c H+J 339 des(1-5)-3-(3-indolyl)propionyl-[AzaGly7, Arg(Me)9]MS10 824.6 824.5 16.0 c S 340 des(1-5)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9]MS10 786.4 786.4 8.5 c S 341 des(1-5)-benzoyl-[AzaGly7, Arg(Me)9]MS10 757.2 757.4 14.8 c S 344 des(1-5)-indole-3-carbonyl-[AzaGly7, Arg(Me)9]MS10 796.5 796.4 14.5 c S 345 des(1-5)-indole-3-acetyl-[AzaGly7, Arg(Me)9]MS10 810.5 810.4 15.2 c S 346 des(1-5)-Ac-[AzaGly7, Arg(Me)9]MS10 695.5 695.4 10.7 c S 347 des(1-5)-n-hexanoyl-[AzaGly7, Arg(Me)9]MS10 751.7 751.5 16.2 c S 348 des(1-5)-Z-[AzaGly7, Arg(Me)9]MS10 787.5 787.4 16.7 c S 349 des(1-5)-Tos-[AzaGly7, Arg(Me)9]MS10 807.5 807.4 15.9 c S 351 des(1-5)-benzoyl-MS10 742.4 742.4 15.1 c A+I 352353 des(1-5)-3-(3-indolyl)propionyl-MS10 809.6 809.4 16.2 c A+I des(1-5)-benzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 796.4 796.4 15.0 c S 354 des(1-5)-3-(3-indolyl)propionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 863.4 863.5 16.2 c S

358 des(1-5)-Ac[AzaGly7, Arg(Me)9, Trp10]MS10 734.4 734.4 11.2 c S 362 des(1-6)-3-phenylpropionyl-[AzaGly7, Arg(Me)9]MS10 638.4 638.4 12.5 c S 364 des(1-5)-2-(Indol-indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9]MS10 839.6 839.5 15.8 c N 366 des(1-5)-n-hexanoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 790.5 790.5 16.5 c S 367 des(1-5)-Z-[AzaGly7, Arg(Me)9, Trp10]MS10 826.5 826.4 16.8 c S 368 des(1-5)-Tos-[AzaGly7, Arg(Me)9, Trp10] MS10 846.6 846.4 16.0 c S 369 des(1-5)-2-(indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 878.9 878.5 16.1 c N

[Table 8]

373 des(1-6)-(2S)-2-Acetoxy-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 735.5 735.4 13.6 c S 374 des(1-6)-Z-[AzaGly7, Arg(Me)9, Trp10]MS10 679.5 679.4 31.2 c S 375 2-Aminoethyl-Gly-[D-Tyr1, Arg(Me)9]MS10 1416.4 1416.7 17.3 e E 378 des(1-6)-diphenylhexanoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 739.4 739.4 15.9 c S 379 des(1-6)-(2S)-2-(3-indolylpropionyloxy)-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 864.7 864.5 18.2 c S 380 des(1-6)-(2S)-2-benzoyloxy-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 797.6 797.4 17.2 c S 385 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10 1204.4 1204.6 8.3 c O 388 des(1-3)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 1026.4 1026.2 8.5 c I 387 Dap-[D-Tyr1, Arg(Me)9]MS10 1402.7 1402.7 17.0 e E 392 des(1-5)-benzoyl[Ala6, AzaGly7, Arg(Me)9, Trp10] MS10 720.5 720.4 11.4 c S 393 des(1-6)-diphenylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 768.7 768.4 16.9 c P 397 Methylthiocarbamoyl-Sar-[D-Tyr1, Arg(Me)9]MS10 1461.2 1460.7 20.0 e E 400 (S)-1-(quinolin-8-yl-carbamoyl)-4-pentylthiocarbamoyl-[D-Tyr1, Arg(Me)9]MS10 1617.9 1617.7 21.7 e E. 408 des(1-6)-1-oxo-isochroman-3-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 719.1 719.4 11.3 c S

412 des(1-6)-(2R)-2-benzoyl-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 796.8 797.4 17.1 c S 417 des(1-6)-Benzylphenethylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 782.9 782.4 17.8 c P 421 des(1-5)-benzoyl-[6ψ7, CH2O, Arg(Me)9, Trp10] MS10 782.2 782.4 22.1 e O 423 des(1-5)-benzoyl-[6ψ7, NHCO, Arg(Me)9, Trp10] MS10 795.4 795.4 19.8 e I+K 428 des(1-6)-Dibenzylaminocarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 783.8 783.4 17.0 c P 431 des(1-5)-benzoyl-[AzaPhe6, AzaGly7, Arg(Me)9, Trp10] MS10 797.7 797.4 15.3 c U 432 des(1-5)-3-(3-pyridyl)propionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 797.8 797.4 9.2 c S 434 des(1-7)-dibenzylaminocarbamoyl-[Arg(Me)9, Trp10]MS10 767.6 767.4 14.5 c R 435 des(1-5)-2-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 797.7 797.4 14.1 c S 436 des(1-5)-4-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 797.8 797.4 8.8 c S 437 des(1-5)-propionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 748.7 748.4 14.4 c S 438 des(1-5)-isobutyryl-[AzaGly7 Arg(Me)9, Trp10]MS10 762.4 762.4 13.7 c S 439 des(1-5)-cyclohexanecarbonyl-[AzaGly7, Arg(Me)9, Trp10] MS10 802.6 802.5 16.3 c S

[Table 9]

440 des(1-5)-phenylacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10 810.1 810.4 15.6 c S 441 des(1-5)-benzoyl-[Pya(2)6, AzaGly7, Arg(Me)9, Trp10] MS10 797.6 797.4 9.5 c S 442 des(1-5)-benzoyl-[Pya(4)6, AzaGly7, Arg(Me)9, Trp10] MS10 797.6 797.4 9.1 c S 443 des(1-5)-2-Methylnicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 811.6 811.4 9.0 c S 444 des(1-5)-5-methylnicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 811.5 811.4 9.2 c S 445 des(1-5)-6-methylnicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 811.4 811.4 8.6 c S 446 des(1-5)-pyrazinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 798.4 798.4 12.4 c S 447 des(1-5)-cyclopropanecarbonyl-[AzaGly7, Arg(Me)9, Trp10] MS10 765.9 766.5 13.0 c S 448 des(1-5)-trifluoroacetyl-[AzaGly7, Arg(Me)9, Trp10]MS10 788.6 788.4 14.6 c S 449 des(1-5)-benzoyl-[Cha6, AzaGly7, Arg(Me)9, Trp10] MS10 802.6 802.5 17.2 c S 450 des(1-5)-Benzyl-[AzaGly7, Arg(Me)9, Trp10]MS10 782.7 782.4 11.2 c H+D 451 des(1-5)-cyclopropanecarbonyl-[Cha6, AzaGly7, Arg(Me)9, Trp10] MS10 765.9 766.5 15.1 c S 452 des(1-5)-(R)-3-hydroxy-2-methylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 777.8 778.4 11.4 c S 453 des(1-5)-2-hydroxyisobutyryl-[AzaGly7, Arg(Me)9, Trp10]MS10 777.9 778.4 11.9 c S 454 des(1-5)-3-furancarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 786.8 786.4 13.7 c S 455 des(1-5)-pyrrole-2-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 785.7 785.4 13.9 c S 459 des(1-5)-4-imidazolecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 786.6 786.4 8.5 c S 460 des(1-5)-4-pyridinecarbonyl-[AzaGly7, Val8, Arg(Me)9, Trp10] MS10 783.5 783.4 6.7 c S 461 des(1-5)-4-pyridinecarbonyl-[AzaGly7, Arg(Me)9, Nal(2)10]MS10 808.5 808.4 11.1 c S 462 des(1-5)-6-Hydroxynicotinoyl-[AzaGly7, Arg(Me)9 Trp10]MS10 813.8 813.4 10.2 c S 463 des(1-5)-8-chloronicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 831.8 831.4 14.3 c S 464 des(1-5)-6-(trifluoromethyl)nicotinoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 865.7 865.4 15.8 c S 466 des(1-5)-2-azetidinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 775.8 775.4 8.9 c h 467 des(1-5)-Dimethylcarbamoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 763.7 763.4 12.5 c H+N 468 des(1-5)-1-azetidinecarbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 775.4 775.4 12.5 e H+N 471 des(1-5)-4-pyridinecarbonyl-[AzaGly7, Arg(Me)9]MS10 758.8 758.5 9.1 c S 472 des(1-5)-4-aminobenzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 811.8 811.4 11.2 c H 473 des(1-5)-4-Aminomethylbenzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 825.8 825.5 9.5 c h

[Table 10]

474 des(1-5)-pyrrole-3-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 785.8 785.4 12.2 c S 475 des(1-5)-pyrimidine-4-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 798.8 798.4 12.2 c S 477 des(1-5)-4-pyridinecarbonyl-[AzaGly7, Orn9, Trp10] MS10 741.6 741.3 8.6 c G+I 478 des(1-5)-4-pyridinecarbonyl-[AzaGly7, Hrp9, Trp10] MS10 797.9 797.4 8.6 c G+I 479 des(1-5)-pyrimidine-2-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 798.8 798.4 11.8 c S 480 des(1-5)-pyridazine-4-carbonyl-[AzaGly7, Arg(Me)9, Trp10]MS10 798.8 798.4 10.7 c S 481 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har9, Trp10] MS10 1204.8 1204.6 8.2 c G 486 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Orn9] MS10 1109.6 1109.6 13.6 e G 487 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Lys9] MS10 1123.5 1123.6 13.5 e G 488 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har9] MS10 1165.6 1165.6 14.1 e G 489 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Har(Me)9] MS10 1179.6 1179.6 13.9 e O 490 des(1)-[D-Tyr2, Pya(4)3, AzaGly7, Arg(Me)9] MS10 1165.6 1165.6 7.6 c h 491 des(1)-[D-Tyr2, D-Pya(4)3, Trp5, AzaGly7, Arg(Me)9, Trp10] MS10 1303.8 1303.6 17.2 e O 492 des(1)-[D-Tyr2, D-Pya(4)3, Ala4, AzaGly7, Arg(Me)9, Trp10] MS10   1181.9 1161.6 14.3 e O 493 des(1)-[D-Tyr2, D-Pya(4)3, Thr4, AzaGly7, Arg(Me)9, Trp10] MS10 1191.9 1191.6 14.2 e O 494 des(1,4)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10 1090.9 1090.6 8.4 c O 495 des(1-3)-[D-Tyr4, Pya(4)5, AzaGly7, Arg(Me)9, Trp10] MS10 1003.9 1003.5 7.6 c O 496 des(1)-[D-Tyr2, D-Pya(4)3, Cha6, Arg(Me)9, Trp10] MS10 1209.8 1209.7 10.4 c E 497 des(1)-[D-Tyr2 D-Pya(4)3, Che6, Ala7, Arg(Me)9, Trp10] MS10 1223.7 1223.7 10.5 c E 498 des(1)-[D-Tyr2 D-Pya(4)3, Ile5, AzaGly7, Arg(Me)9, Trp10] MS10 1230.7 1230.7 16.8 c O 499 des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9, Trp10]MS10 1025.3 1025.5 13.6 c T 500 des(1-3)-3-phenylpropionyl-[Ala4, AzaGly7, Arg(Me)9, Trp10] MS10 982.5 982.5 15.1 c T 501 des(1)-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1218.7 1218.6 14.2 e O 502 des(1)-[D-Tyr2, Pya(4)3, Ala4, AzaGly7, Arg(Me)9, Trp10] MS10 1161.4 1161.6 14.0 e O

503 des(1)-[D-Tyr2, D-Trp3, Ala4, AzaGly7, Arg(Me)9, Trp10] MS10 1199.3 1199.6 17.8 e O 504 [Acp1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10 1278.6 1278.5 8.1 c H 505 des(1-3)-3-phenylpropionyl-[Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1040.0 1039.5 13.9 c T 506 des(1-3)-3-phenylpropionyl-[Ile5, AzaGly7, Arg(Me)9, Trp10] MS10 1052.0 1051.6 17.6 c T 507 des(1-3)-3-phenylpropionyl-[Trp6, AzaGly7, Arg(Me)9, Trp10] MS10 1064.2 1064.5 13.7 c T

[Table 11]

508 des(1-3)-3-phenylpropionyl-[Phe(4F)6, AzaGly7, Arg(Me)9, Trp10]MS10 1043.2 1043.5 14.1 c T 509 des(1-3)-benzoyl-[AzaGly7, Arg(Me)9, Trp10]MS10 997.8 997.5 12.4 c T 510 des(1-3)-Ac-[AzaGly7, Arg(Me)9, Trp10]MS10 935.9 935.5 9.5 c T 511 des(1)-[D-Tyr2, D-Trp3, Ala4, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1213.6 1213.6 17.9 e o 512 des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1256.7 1256.6 17.0 e O 513 des(1)-[D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg(Me)9, Trp10] MS10 1213.8 1213.6 18.5 e O 514 des(1)-[D-Tyr2, D-Phe3, Ala4, AzaGly7, Arg(Me)9, Trp10] MS10 1160.8 1160.6 17.9 e O 515 des(1)-[D-Tyr2, D-Pya(4)3, Val5, AzaGly7, Arg(Me)9, Trp10] MS10 1216.8   1216.6 15.7 e O a: 0-70% AcCN/35min, flow rate 1ml/min, Wakosil-II 5C18 HG (4.6×100mm) b: 0-70% AcCN/35min, flow rate 1ml/min, YMC ODS AM-301 (4.6×100mm) c: 20-70% AcCN/25min, flow rate 1ml/min, YMC ODS AM-301 (4.6×100mm) d: 5-75% AcCN/35min, flow rate 1ml/min, Wakosil-II 5C18 HG (4.6×100mm) e: 0-50% AcCN/25min, flow rate 1ml/min, Wakosil-II 5C18 HG (4.6×100mm) Only compound No. 1 exhibited an M ⁺ value

The structures of the compounds synthesized as in Examples 1 to 24 and the physicochemical properties of these compounds are shown in Table 12 below.

[Table 12]

Comp. No. M+H+(obs.) M+H+(cal.) HPLC(min.) HPLC mode 516 Ac-des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10 1207.8 1207.6 9.2 c 517 des(1-3)-3-Phenylpropionyl-[Hyp5, AzaGly7, Arg(Me)9, Trp10] MS10 1051.6 1051.5 13.7 c 518 des(1-3)-3-Phenylpropionyl-[Cha6, Are(Me)9, Trp10]MS10 1030.5 1030.6 15.8 c 519 des(1-3)-Phenylacctyl-[AzaGly7, Arg(Me)9, Trp10] MS10 1011.5 1011.5 12.7 c 521 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7] MS10 1151.5 1151.6 13.4 e 522 des(1-3)-Benzoyl-[Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1011.9 1011.5 12.7 c 523 des(1-3)-Benzoyl-[Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10] MS10 1028.8 1029.5 13.3 c 524 des(1-3)-3-Phenylpropionyl-[Pro5, AzaGly7, Arg(Me)9, Trp10] MS10 1036 1035.6 15.8 c 527 des(1)-[D-Tyr2, D-Pya(4)3, Hyp5, AzaGly7, Arg(Me)9, Trp10] MS10 1230.5 1230.6 14.3 c 528 des(1)-[D-Tyr2, D-Pya(4)3, Pro5, AzaGly7, Arg(Me)9, Trp10] MS10 1214.7 1214.6 15.7 e 529 des(1)-[D-Tyr2, D-Pya(4)3, Tla5, AzaGly7, Arg(Me)9, Trp10] MS10 1230.7 1230.7 16.5 e 530 des(1)-[D-Tyr2, D-Pya(4)3, Phg5, AzaGly7, Arg(Me)9, Trp10] MS10 1250.6 1250.6 16.8 c 531 des(1-3)-3-Phenylpropionyl-[Pic(2)5, AzaGly7, Arg(Me)9, Trp10] MS10 1049.6 1049.6 16.4 c 532 des(1-3)-3-Phenylpropiony1-[Aza(2)5, AzaGly7, Arg(Me)9, Trp10] MS10 1021.8 1021.5 14.4 c 533 des(1-3)-3-Phenylpropionyl-[D-Pro5, AzaGly7, Arg(Me)9, Trp10] MS10 1035.7 1035.6 15.2 c 534 des(1-3)-Cyclopropanocarbonyl-[AzaGly7, Arg(Me)9, Trp10] MS10 961.6 961.5 10.7 c 535 des(1-3)-2-Nanhthoyl-[AzaGly7, Arg(Me)9, Trp10] MS10 1047.6 1047.5 14.7 c 536 [Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10 1360.3 1360.7 14 e 537 Arg-[Arg1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10   1516.5   1516.8 13.4 e 538 Arg-[Acp1, D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9, Trp10] MS10 1473.8 1473.8 13.9 e 539 des(1)-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg(Me)9, Trp10] MS10 1254.7 1254.7 18.7 e 540 des(1)-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)8, Trp10] MS10 1242.4 1242.6 11.8 c 541 D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1525.8 1525.8 16.7 e 542 D-Arg-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me), Trp10] MS10 1681.9 1681.9 16.3 e 545 des(1-3)-Benzoyl-[Phe(4F)6, AzaGly7, Arg(Me)9, Trp10] MS10 1015.7 1015.5 13 c 546 des(1-3)-3-Phenylpropionyl-[Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10] MS10 1067.6 1067.5 15.2 c 547 des(1)-[D-Tyr2, D-Pya(4)3, Ser(Ac)5, AzaGly7, Arg(Me)9, Trp10] MS10 1246.6 1246.7 8.4 c 548 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9.10ψ, CSNH] MS10 1181.5 1181.6 14.9 e 550 Ac-des-(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1298.7   1298.6 13.6 c 551 Ac-D-Arg-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1567.8 1567.8 12.4 c 552 D-Dap-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1455.8 1455.8 11.5 c 553 D-Nle-[Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1482.5 1482.8 13.3 c 554 D-Arg-[b-Ala1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1483.7 1483.8 16.5 e 555 D-Arg-[g-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1497.7 1497.8 16.6 e 556 D-Arg-D-Arg-[g-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1654   1653.0 15.7 e

Comp, No. structure M+H+(obs.) M+H+(cal.)  HPLC(min.) HPLC mode Syn. Proc. 584 des(1)-Ac-[D-Tyr2, D-Trp3, Dap(Ac)4, AzaGly7, Arg(Me)9, Trp10] MS10 1298.7 1298.5 18.7 e x 585 des(1)-Ac-[D-Tyr2, D-Trp3, Dap(For)4, AzaGly7, Arg(Me)9, Trp10] MS10 1284.7 1284.6 17.9 c x 586 des(1)-Ac-[D-Tyr2, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10]MS10 W 589 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Nal(2)10]MS10 1309.6 1309.6 15.2 c W 590 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Thi10] MS10 1265.5 1265.6 13.4 c W 591 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Tyr10] MS10 1275.5 1275.6 12.2 c W 592 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Phe(4F)10]MS10 1277.5 1277.6 14 c W 594 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Hph10] MS10 1273.6 1273.6 14.6 c W 597 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10] MS10 1298.8 1298.7 14.1 c W 598 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Arg(Me)9, Trp10] MS10 1297.5 1297.6 18.5 e H+W 599 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Orn9, Trp10] MS10 1242.4 1242.6 17.8 c G+W 600 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Trp10] MS10 1284.7 1284.6 17.9 e G+W 601 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, D-Phe6, Arg(Me)9, Trp10] MS10 1297.6 1297.6 18.2 c H+W 602 des(1)-Ac-[D-NMeTyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1312.7 1312.7 19 c W 603 des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, D-Phe6, AzaGly7, Arg(Me)9, Trp10] MS1 1260.6 1260.6 15.3 e W 604 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1438.6 1438.6 20.5 e G+W 605 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1329.4 1329.6 18.7 e G+W 607 des(1)-Ac-[D-Tyt2, D-Trp3, Thr5, AzaGly7, Arg(Me2)8sym9, Trp10] MS10 1312.9 1312.7 18.1 e W 608 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me2)sym9, Trp10] MS10 1312.3 1312.7 18.1 e W 609 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1312.8 1312.7 17.7 e W 610 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys(Me)9, Trp10] MS10 1284.8 1284.7 17.7 e G+W 611 des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1260.8 1260.6 14.4 e W 612 des(1)-For-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1284.7 1284.6 17.8 e T+W 613 des(1)-Propionyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1312.6 1312.7 18.3 e T+W 614 des(1)-Amidino-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1298.4 1298.7 16.9 e J+W 615 des(1)-Ac-[Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1299 1298.6 13.9 c W 616 des(1)-Ac-[D-Ala2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1206.8 1206.4 13.1 c W 617 des(1)-Ac-[D-Leu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1248.9 1248.7 15.5 c W 618 des(1)-Ac-[D-Phe2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1282.7 1282.6 15.8 c W 619 des(1)-Ac-[D-Nal(1)2, D-Trp3, Thr5, AzaGly7, Atg(Me)9, Trp10] MS10 1332.6 1332.7 17.6 c W 620 des(1)-Ac-[D-Nal(2)2, D-Trp3, Thr5, AzaGly7, Atg(Me)9, Trp10] MS10 1332.4 1332.7 17.7 c W 621 des(1)-Ac-[D-Lys2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1283.5 1263.7 11.3 c W 622 des(1)-Ac-[D-Glu2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1264.6 1264.4 12.7 c W 623 des(1)-Ac-[D-Tyr2, Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1298.9 1298.6 14.2 c W 624 des(1)-Ac-[D-Tyr2, Pya(4)3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1260.8 1260.6 10.2 c W

625 des(1)-Ac-[D-Tyr2, D-Ala3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1183.8 1163.8 11.4 c W 626 des(1)-Ac-[D-Tyr2, D-Leu3, Thr5, AzaGrg7, Arg(Me)8, Trp10] MS10 1226 1225.6 13.3 c W 627 des(1)-Ac-[D-Tyr2, D-Phe3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1259.9 1259.6 13.8 c W 628 des(1)-Ac-[D-Tyr2, D-Thr3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1213.9 1213.6 11.1 c W 629 des(1)-Ac-[D-Tyr2, D-Lys3, Thr5, AzaGly7, Arg(Me)8, Trp10] MS10 1240.9 1240.7 10.1 c W 630 des(1)-Ac-[D-Tyr2, D-Glu3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1241.9 1241.6 11.2 c W 631 des(1)-Ac-[D-Tyr2, D-Thr3, Thr5, Ala6, AzaGly7, Arg(Me)9, Trp10] MS10 1222.9  1222.6 11.6 c W 632 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Leu6, AzaGly7, arg(Me)9, Trp10] MS10 1265 1264.7 13.5 c W 633 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Lys6, AzaGly7, Arg(Me)9, Trp10] MS10 1279.8 1279.7 10.4 c W 634 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Glu6, AzaGly7, Arg(Me)9, Trp10] MS10 1280.8 1280.6 11.5 c W 635 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Pya(4)6, AzaGly7, Arg(Me)9, Trp10] MS10 1299.9   1299.6 10.5 c W 636 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, MePhe6, AzaGly7, Arg(Me)9, Trp10] MS10 1312.4 1312.7 15.4 c W 637 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10] MS10 1316.5 1316.6 14.4 c W 638 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Phe(4F)6, AzaGly7, Arg(Me)9, Trp10] MS10 1278.6 1278.6 10.7 c W 639 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys9, Trp10] MS10 1256.9 1256.6 17.5 e G+W 640 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, D-Leu8, Arg(Me)9, Trp10] MS10 1298.7   1298.6 17.6 e W 641 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ala8, Arg(Me)9, Trp10] MS10 1256.9 1256.6 16.5 e W 642 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Val8, Arg(Me)9, Trp10] MS10 1284.5 1284.6 17.4 e W 643 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Phe8, Arg(Me)9, Trp10] MS10 1332.4 1332.6 18.3 c W 644 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ser8, Arg(Me)9, Trp10] MS10 1272.9 1272.6 15.5 e W 645 des(1)-Ac-[D-Tyr2, D-Trp3 Thr5, AzaGly7, Her9, Trp10] MS10 1299.1   1298.6 17.7 e G+W 646 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Har(Me)9, Trp10]MS10 1313.1 1312.7 17.9 e W 647 des(1)-Ac-[D-Tyr2, D-Trp3, Asp4, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1299.9   1299.6 18.2 e W 648 [Gly1 D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1313.6 1313.7 16 e W 649 Ac-[Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1355.9 1355.7 17.4 c W 650 [D-Tyr1, D-Tyr2 D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1419.8 1418.7 16.6 e W 651 Ac-[D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1461.4 1461.7 18 e W 652 pGlu-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 1367.4 1367.7 17.6 e W 653 des(1)-Ac-[D-Tyr2, D-Trp3, D-Aan4, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1296.8   1296.6 18.2 c W 654 des(1)-Ac-[D-Tyr2, D-Trp3, D-Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1298.8   1298.6 17.6 e W 655 des(1)-Ac-[D-Tyr2, D-Trp3, MeAsn4, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1312.8 1312.7 18.3 e W 656 des(1)-Ac-[D-Tyr2, D-Trp3, MeSer5, AzaGly7, Arg(Me)9, Trp10] MS10 1298.8   1298.6 17.8 e W 657 des(1)-Ac-[D-Tyr2, Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1209.2 1209.6 12.4 c W 658 des(1)-Ac-[D-Tyr2, D-Pya(2)3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1260.3 1260.6 10.4 c W 659 des(1)-Ac-[D-Tyr2, D-Trp3, allo-Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1298.8   1298.6 17.9 e W 660 des(1)-Ac-[D-Tyr2, D-Pya(3), Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1260.8 1260.6 10.3 c W

681 des(1)-Ac-[D-Tyr2, D-Pro3, Thr5, AzaGly7, Arg(Me)9, Trp10) MS10 1209.8 1209.6 11.5 c W 662 des(1)-Ac-[D-Tyr2, Tie3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS1O 1271.4 1271.4 13.9 c W 663 des(1)-Ac-[D-Trp2, D-Trp3, Thr5, AzaGly7, Arp(Me)9, Trp10] MS10 1321.7 1321.7 15.9 c W 664 des(1)-Ac-[Tyr2, Thr5, AzaGly7, Arg(Me)Trpl0] MS10 1298.7 1298.6 14.1 c W 685 des(1-2)-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10]MS10 1093.7 1093.6 11.1 c O 666 des(1-2)-Ac-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1135.7 1135.6 13.4 c T+W 667 des(1-2)-Hexanoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1191.4 1191.6 17.2 c T+W 668 des(1-2)-Cyclohexanecarbonyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS 1203.3 1203.6 17.1 c T+W 669 des(1-2)-Benzoyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1197.8 1197.6 16 c T+W 670 des(1-2)-3-Pyridinepropionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me), Trp10] MS1 1226.7 1226.6 11.5 c T+W 671 des(1-2)-Adipionyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1221.6 1221.6 13.5 c T+W 672 des(1)-Ac-[D-Tyr2, MeTrp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1312.9 1312.7 14.5 c W 674 des(1)-Ac-[Acp2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1206.7 1206.7 11.5 c T+W 675 [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1419.6 1419.7 16.8 e W 676 Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1461.4 1461.7 18 e W 677 Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Nva8, Arg(Me)9, Trp10] MS10 1284.9 1284.6 17.1 e W 678 Ac-des(1)-[D-Tyr2, D-Trp3, Thr5, AzaGyl7, Ile8, Arg(Me)9, Trp10] MS10 1298.9 1298.6 17.8 e W 679 des(1-2)-Amidino-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1135.7 1135.5 11.7 c J+W 680 des(1-2)-Glycoloyl-[D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1151.9 1151.6 12.9 c W 681 des(1)-Glycolyl-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, Trp10] MS10 1314.8 1314.6 13.5 c W 682 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Gln8, Arg(Me)9, Trp10] MS10 1313.9 1313.6 15.7 e W 685 des(1)-Ac-[D-Tyr2, D-Pya(4)3, Thr5, AzaGly7, Arg(Me)9] MS10 1221.8 1221.6 9.9 c W 686 des(1)-Ac-[D-Tyr2, D-Trp3, Gly4, AzaGly7, Arg(Me)9, Trp10] MS10 1227.8 1227.6 14.2 c W 688 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Pya(4)9, Trp10] MS10 1276.8 1276.6 13.9 c W 689 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg(Me)9, D-Trp10] MS10 1298.8 1298.6 13.6 c W 691 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr6, AzaGly7, Arg(Me)9, Trp10] MS10 1314.4 1314.6 12.3 c W 692 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Trp6, AzaGly7, Arg(Me)9, Trp10] MS10 1337.5 1337.7 14 c W 693 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Tyr(Me)6, AzaGly7, Arg(Me)9, Trp10] MS10 1328.9 1328.7 13.9 c W 684 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Nal(2)6, AzaGly7, Arg(Me)9, Trp10] MS10 1348.9 1348.7 15.7 c W 695 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Thi6, AzaGly7, Arg(Me)9, Trp10] MS10 1304.7 1304.6 13.6 c W 696 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Cha6, AzaGly7, Arg(Me)9, Trp10] MS10 1304.9 1304.7 15.3 c W 698 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Abu8, Arg(Me)9, Trp10] MS10 1270.7 1270.6 16.7 e W 699 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, AzaGly7, rMeLeu8, Ayg(Me)9, Trp10] MS10 1312.6 1312.7 18.4 e W 700 des(1)-Ac-[D-Tyr2, D-Trp3, Thr5, Aib8, Arg(Me)9, Trp10] MS10 1269.9 1269.6 16.8 e E 701 des(1)-Ac-[D-Tyr2, D-Trp3, Dap4, AzaGly7, Arg(Me)9, Trp10] MS10 1257 1256.6 16.7 e W 702 des(1)-Ac-[D-Tyr2, D-Trp3, Asp(NHMc)4, Thr5, AzaGly7, Arg(Me)9, Trp10] MS 1312.8 1312.7 17.9 e W

Formulation Example 1:

(1) Compound No. 305 10.0mg

(2) Lactose 60.0mg

(3) Corn starch 35.0mg

(4) Gelatin 3.0mg

(5) Magnesium stearate 2.0mg

Using 0.03 ml of a 10% aqueous gelatin solution (corresponding to 3.0 mg of gelatin), pass 1 mm mesh of a mixture of 10.0 mg of the compound No. 305, 60.0 mg of lactose, and 35.0 mg of cornstarch through a 1 mm mesh, and dry at 40° C. Then sieve again. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting tablet cores were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide talc, and gum arabic. The coated tablets were polished with yellow beeswax to obtain coated tablets.

Formulation Example 2

(1) Compound No. 305 10.0mg

(2) Lactose 70.0mg

(3) Corn starch 50.0mg

(4) Soluble starch 7.0mg

(5) Magnesium stearate 3.0mg

A mixture of 10 mg of compound No. 305 and 3.0 mg of magnesium stearate was granulated using 0.07 ml of an aqueous solution of soluble starch (corresponding to 7.0 mg of soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of cornstarch. The mixture is compressed into tablets.

Formulation Example 3

(1) Compound No. 305 5.0mg

(2) Salt (salt) 20.0mg

(3) Distilled water to add the total volume to 2ml

After dissolving 5.0 mg of the compound No. 305 and 20.0 mg of the salt in distilled water, water was added to the solution to make up the total volume to 2.0 ml. The solution is filtered and filled aseptically into 2 ml ampoules. After sterilizing and sealing the ampoule, a solution for injection is obtained.

Formulation Example 4:

(1) Compound No. 550 10.0mg

(2) Lactose 60.0mg

(3) Corn starch 35.0mg

(4) Gelatin 3.0mg

(5) Magnesium stearate 2.0mg

Using 0.03 ml of a 10% aqueous gelatin solution (equivalent to 3.0 mg gelatin), pass a mixture of 10.0 mg of compound number 550, 60.0 mg of lactose, and 35.0 mg of cornstarch through a 1 mm mesh sieve, and dry at 40°C. Then sieve again. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting tablet cores are coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with yellow beeswax to obtain coated tablets.

Formulation Example 5

(1) Compound No. 550 10.0mg

(2) Lactose 70.0mg

(3) Corn starch 50.0mg

(4) Soluble starch 7.0mg

(5) Magnesium stearate 3.0mg

A mixture of 10 mg of compound number 550 and 3.0 mg of magnesium stearate was granulated using 0.07 ml of an aqueous solution of soluble starch (equivalent to 7.0 mg of soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of cornstarch. The mixture is compressed into tablets.

Formulation Example 6

(1) Compound No. 550 5.0mg

(2) Salt 20.0mg

(3) Distilled water to add the total volume to 2ml

After dissolving 5.0 mg of Compound No. 550 and 20.0 mg of the salt in distilled water, water was added to the solution to make up the total volume to 2.0 ml. The solution is filtered and filled aseptically into 2 ml ampoules. After sterilizing and sealing the ampoule, a solution for injection is obtained.

Formulation Example 7:

(1) Compound No. 562 10.0mg

(2) Lactose 60.0mg

(3) Corn starch 35.0mg

(4) Gelatin 3.0mg

(5) Magnesium stearate 2.0mg

Using 0.03 ml of a 10% aqueous gelatin solution (equivalent to 3.0 mg gelatin), pass a mixture of 10.0 mg of the compound No. 562, 60.0 mg of lactose, and 35.0 mg of cornstarch through a 1 mm mesh sieve, and dry at 40° C. Then sieve again. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting tablet cores are coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with yellow beeswax to obtain coated tablets.

Formulation Example 8

(1) Compound No. 562 10.0mg

(2) Lactose 70.0mg

(3) Corn starch 50.0mg

(4) Soluble starch 7.0mg

(5) Magnesium stearate 3.0mg

A mixture of 10 mg of compound No. 562 and 3.0 mg of magnesium stearate was granulated using 0.07 ml of an aqueous solution of soluble starch (corresponding to 7.0 mg of soluble starch), then dried and mixed with 70.0 mg of lactose and 50.0 mg of cornstarch. The mixture is compressed into tablets.

Formulation Example 9

(1) No. 562 compound 5.0mg

(2) Salt 20.0mg

(3) Distilled water to add the total volume to 2ml

After dissolving 5.0 mg of Compound No. 562 and 20.0 mg of the salt in distilled water, water was added to the solution to make up the total volume to 2.0 ml. The solution is filtered and filled aseptically into 2 ml ampoules. After sterilizing and sealing the ampoule, a solution for injection is obtained.

Formulation Example 10:

(1) No. 571 compound 10.0mg

(2) Lactose 60.0mg

(3) Corn starch 35.0mg

(4) Gelatin 3.0mg

(5) Magnesium stearate 2.0mg

Using 0.03 ml of a 10% aqueous gelatin solution (equivalent to 3.0 mg gelatin), pass a mixture of 10.0 mg of the compound No. 571, 60.0 mg of lactose, and 35.0 mg of cornstarch through a 1 mm mesh sieve, and dry at 40° C. Then sieve again. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting tablet cores were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with yellow beeswax to obtain coated tablets.

Formulation Example 11

(1) Compound No. 571 10.0mg

(2) Lactose 70.0mg

(3) Corn starch 50.0mg

(4) Soluble starch 7.0mg

(5) Magnesium stearate 3.0mg

Using 0.07 ml of an aqueous solution of soluble starch (equivalent to 7.0 mg soluble starch), a mixture of 10 mg of compound No. 571 and 3.0 mg of magnesium stearate was granulated, dried and mixed with 70.0 mg of lactose and 50.0 mg of cornstarch. The mixture is compressed into tablets.

Formulation Example 12

(1) Compound No. 571 5.0mg

(2) Salt 20.0mg

(3) Distilled water to add the total volume to 2ml

After dissolving 5.0 mg of the compound No. 571 and 20.0 mg of the salt in distilled water, water was added to the solution to make up the total volume to 2.0 ml. The solution is filtered and filled aseptically into 2 ml ampoules. After sterilizing and sealing the ampoule, a solution for injection is obtained.

Formulation Example 13:

(1) Compound No. 579 10.0mg

(2) Lactose 60.0mg

(3) Corn starch 35.0mg

(4) Gelatin 3.0mg

(5) Magnesium stearate 2.0mg

Using 0.03 ml of a 10% aqueous gelatin solution (equivalent to 3.0 mg of gelatin), pass a mixture of 10.0 mg of compound No. 579, 60.0 mg of lactose, and 35.0 mg of cornstarch through a 1 mm mesh sieve, and dry at 40° C. Then sieve again. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting tablet cores are coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with yellow beeswax to obtain coated tablets.

Formulation Example 14

(1) Compound No. 579 10.0mg

(2) Lactose 70.0mg

(3) Corn starch 50.0mg

(4) Soluble starch 7.0mg

(5) Magnesium stearate 3.0mg

A mixture of 10 mg of compound No. 579 and 3.0 mg of magnesium stearate was granulated using 0.07 ml of an aqueous solution of soluble starch (equivalent to 7.0 mg of soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of cornstarch. The mixture is compressed into tablets.

Formulation Example 15

(1) Compound No. 579 5.0mg

(2) Salt 20.0mg

(3) Distilled water to add the total volume to 2ml

After dissolving 5.0 mg of the compound No. 579 and 20.0 mg of the salt in distilled water, water was added to the solution to make up the total volume to 2.0 ml. The solution is filtered and filled aseptically into 2 ml ampoules. After sterilizing and sealing the ampoule, a solution for injection is obtained.

Formulation Example 16:

(1) Compound No. 585 10.0mg

(2) Lactose 60.0mg

(3) Corn starch 35.0mg

(4) Gelatin 3.0mg

(5) Magnesium stearate 2.0mg

Using 0.03 ml of 10% aqueous gelatin solution (equivalent to 3.0 mg gelatin), pass 1 mm mesh of a mixture of 10.0 mg of the compound No. 585, 60.0 mg of lactose, and 35.0 mg of cornstarch into granules, and dry at 40°C Then sieve again. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting tablet cores are coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with yellow beeswax to obtain coated tablets.

Formulation Example 17

(1) Compound No. 585 10.0mg

(2) Lactose 70.0mg

(3) Corn starch 50.0mg

(4) Soluble starch 7.0mg

(5) Magnesium stearate 3.0mg

A mixture of 10 mg of compound 585 and 3.0 mg of magnesium stearate was granulated using 0.07 ml of an aqueous solution of soluble starch (equivalent to 7.0 mg of soluble starch), then dried and mixed with 70.0 mg of lactose and 50.0 mg of cornstarch. The mixture is compressed into tablets.

Formulation Example 18

(1) Compound No. 585 5.0mg

(2) Salt 20.0mg

(3) Distilled water to add the total volume to 2ml

After dissolving 5.0 mg of the compound No. 585 and 20.0 mg of the salt in distilled water, water was added to the solution to make up the total volume to 2.0 ml. The solution is filtered and filled aseptically into 2 ml ampoules. After sterilizing and sealing the ampoule, a solution for injection is obtained.

Test Example 1

Determination of binding activity to hOT7T175 receptor

(1) Preparation of Cy-5-labeled transferin (40-54)

Into the synthetic peptide with 40-50 amino acid sequence in the amino acid sequence of transferin, introduce Cy-5 through the ε-amino group of lysine located at its amino terminal, and then obtain the carboxyl terminal by the synthetic technology of Amersham Bioscience. products of amidation. Binding inhibition experiments were performed using this synthetic peptide.

Sequence: (Cy-5)-KDLPNYNWNSFGLRF- _NH2

(2) Use the test compound, Cy-5-labeled transferin (40-54) and h0T7T175-expressing CHO cells for binding inhibition experiments

hOT7T175-expressing CHO cells were cultured in MEM-α medium (nucleic acid-free) containing 10% dialyzed serum. Media was removed and adherent cells were washed with PBS. Then PBS containing 5 mM EDTA was added. Scrape the cells from the culture flask using a cell scraper.

After centrifugation, the cells were suspended to a concentration of 1.11×10 ⁵ cells/ml with assay buffer (10 mM HEPES pH 7.4, 140 mM NaCl, 2.5 mM CaCl ₂ , 3 mM MgCl ₂ , 0.5% BSA, 0.01% NaN ₃ ), and poured into the Cy-5-labeled transferin (40-54) was added to the suspension to make the final concentration 1 nM. To each well of a 96-well black transparent bottom microplate (Black Clear Bottom Microplate) (purchased from Biosystems), 10 μL of assay buffer containing 1% dimethyl sulfoxide for the determination of total binding was added, 10 μL of 10 μM unlabeled peptide (with the same amino acid sequence as the labeled peptide) diluted with assay buffer for the determination of non-specific binding, 10 μL of test compound diluted with assay buffer for determination of the binding inhibitory activity of the test compound , and then add 90 μL of cell suspension respectively. After 1 hour, the binding level of Cy-5-labeled transferin (40-54) to the cells was detected by FMAT 8100 HTS system (purchased from Biosystems). Specific binding was obtained by subtracting non-specific binding from total binding. The binding inhibitory activity of the test compound was expressed as the ratio of the value obtained by subtracting the measured value when the test compound was added from the total binding to the specific binding. The receptor binding activities of the test compounds are shown in Tables 13 to 18.

[Table 13]

Compound No. IC50(M) 1 Transferin 1.7E-07 3 MS10 6.5E-09 4 des(1)-MS10 2.6E-07 17 [Pya(4)10]MS10 6.6E-12 18 [Tyr(Me)10]MS10 7.7E-09 19 [Phe(2F)10]MS10 8.6E-09 twenty three [Tyr5] MS10 4.0E-07 twenty four [Leu5] MS10 8.3E-10 30 Acetyl-MS10 3.1E-08 31 Fmoc-MS10 9.3E-07 32 Leu-Pro-Asn-MS10 2.5E-08 39 [D-Asn4] MS10 8.3E-07 40 [D-Trp3] MS10 1.9E-08 41 [D-Asn2] MS10 2.1E-07 42 [D-Tyr1] MS10 5.7E-08 44 [Lys9] MS10 1.9E-07 50 [Ala7] MS10 1.9E-07 54 des(1-2)-Fmoc-MS10 4.5E-07 57 [Asp2]MS10 1.0E-07 58 [Tyr2] MS10 1.6E-08 59 [Leu2] MS10 3.4E-07 60 [Pya(3)10]MS10 1.7E-07 61 [Phe(4F)10]MS10 1.3E-08 67 [Ala3] MS10 2.7E-08 68 [Leu3] MS10 7.7E-09 69 [Ser3] MS10 8.3E-08 70 [Asp3]MS10 2.0E-07 71 [Lys3] MS10 6.6E-08 72 [Ala1] MS10 5.4E-07 73 [Leu1] MS10 2.2E-07 75 [Asp1] MS10 8.8E-07

[Table 14]

77 [Phe(4CN)10]MS10 7.4E-09 78 [Trp(CHO)3,Phe(4CN)10]MS10 2.5E-08 82 [Arg(Me)9]MS10 4.1E-09 83 [Arg(Me2)asy9]MS10 2.5E-08 97 [Har9] MS10 3.7E-07 101 [Ser7] MS10 1.0E-07 105 [Nle8] MS10 8.8E-07 107 [Val8]MS10 1.2E-07 109 [Tyr10] MS10 2.3E-08 110 [Nal(2)10]MS10 2.4E-08 111 [Phe(F5)10]MS10 1.4E-07 112 [Cha10] MS10 3.7E-07 114 des(1-3)-3-(3-1indolyl)propionyl-MS10 5.5E-07 128 [10ψ,CSNH]MS10 5.5E-08 129 [Arg(Me2)sy9]MS10 8.3E-08 130 [Phe(4Cl)10]MS10 4.2E-08 131 [Phe(4NH2)10]MS10 1.2E-07 132 [Phe(4NO2)10]MS10 9.3E-08 133 [Nal(1)10]MS10 3.3E-07 134 [Trp10] MS10 1.1E-07 141 [D-Tyr1, Arg(Me)9]MS10 5.1E-08 142 [D-Tyr1, D-Trp3, Arg(Me)9] MS10 2.6E-08 143 [D-Trp3, Arg(Me)9]MS10 7.7E-09 145 des(1-2)-Fmoc-[Arg(Me)9]MS10 1.2E-07 146 [10ψ, CSNH, D-Tyr1] MS10 3.7E-07 150 [Tyr6] MS10 3.2E-07 151 [Nal(1)6]MS10 3.0E-07 152 [Nal(2)6]MS10 1.8E-07 153 [Phe(F5)6]MS10 3.9E-07 154 [Phe(4F)6]MS10 6.0E-08 156 [Cha6] MS10 4.9E-08 163 [6ψ7,CH2NH]MS10 2.5E-07 166 [6ψ7,CSNH]MS10 9.4E-09 169 [D-Tyr1, Ala3, Arg(Me)9] MS10 1.6E-07 170 [D-Tyr1, Ser3, Arg(Me)9] MS10 2.6E-07

[Table 15]

171 [D-Tyr1, Cha3, Arg(Me)9] MS10 1.1E-07 174 [D-Tyr1, Arg(Me)9, Trp10] MS10 4.2E-07 176 [AzaGly7] MS10 5.2E-08 181 [D-Tyr1, Cha3, 6, Arg(Me)9] MS10 1.9E-08 182 [D-Tyr1, Cha3, 6, Arg(Me)9, Trp10] MS10 9.8E-08 186 [Trp(CHO)10]MS10 4.6E-07 187 [Abu8] MS10 7.2E-07 189 [Ala(3-Bzt)10]MS10 2.3E-07 190 [D-Tyr1, Cha3, AzaGly7, Arg(Me)9] MS10   1.2E-08 191 [D-Tyr1, Ser3, AzaGly7, Arg(Me)9] MS10 3.0E-07 192 [D-Tyr1, Arg(Et)9]MS10 5.3E-07 193 [D-Tyr1, Arg(n-Pr)9] MS10 9.2E-07 194 [D-Tyr1, Arg(Ac)9]MS10 2.1E-07 197 [Phe(3F)10]MS10 1.7E-07 198 [Phe(3,4F2)10]MS10 1.7E-07 199 [Phe(3,4Cl2)10]MS10 4.7E-07 200 [Phe(3CF3)10]MS10 3.4E-07 201 [Ala(2-Qui)10]MS10 8.2E-07 203 [D-Tyr1, Cha6, Arg(Me)9] MS10 3.7E-08 204 [D-Tyr1, Ala7, Arg(Me)9] MS10 6.8E-07 205 [D-Tyr1, Thr3, Arg(Me)9] MS10 2.6E-07 206 [D-Tyr1, Ile3, Arg(Me)9] MS10 8.5E-08 208 [D-Tyr1, Thr4, Arg(Me)9] MS10 8.3E-07 210 [D-Tyr1, Ala4, Arg(Me)9] MS10 7.3E-07 211 [D-Tyr1, Thr5, Arg(Me)9] MS10 4.4E-08 212 [D-Tyr1, Ala5, Arg(Me)9] MS10 3.6E-08 213 [D-Tyr1, Val8, Arg(Me)9] MS10 1.9E-07 214 [D-Tyr1, Gln2, Arg(Me)9] MS10 3.9E-07 215 [D-Tyr1, Thr2, Arg(Me)9] MS10 2.5E-07 216 des(1)-[D-Asn2, Arg(Me)9]MS10 7.0E-07 217 des(1)-[D-Tyr2, Arg(Me)9]MS10 2.5E-07 220 [Arg(Et)9]MS10 3.3E-07 221 [D-Tyr1, Thr3, AzaGly7, Arg(Me)9] MS10 9.5E-08 222 des(1)-[D-Tyr2, AzaGly7, Arg(Me)9] MS10 3.3E-08 223 des(1-2)-[D-Trp3, Arg(Me)9]MS10 7.6E-07

[Table 16]

224 des(1)-[D-Tyr2, D-Trp3, Arg(Me)9] MS10 1.4E-07 225 des(1)-[D-Asn2, D-Trp3, Arg(Me)9] MS10 4.1E-07 226 des(1)-[D-Tyr2, Ser3, Arg(Me)9] MS10 1.0E-07 227 des(1)-[D-Tyr2,Thr3,Arg(Me)9]MS10 4.8E-08 228 des(1)-[D-Tyr2, Ile3, Arg(Me)9] MS10 4.0E-08 229 [D-Tyr1, Val3, Arg(Me)9] MS10 1.3E-07 230 [D-Tyr1, D-Asn2, Arg(Me)9] MS10 2.5E-07 231 [D-Tyr1, D-Asn2, D-Trp3, Arg(Me)9] MS10 5.5E-08 232 [D-Tyr1, AzaGly7, Arg(Me)9] MS10 4.9E-08 233 [D-Tyr1, Ile3, AzaGly7, Arg(Me)9] MS10 2.3E-08 234 [D-Tyr1, Val3, AzaGly7, Arg(Me)9] MS10 4.7E-08 235 [D-Tyr1, Ala3, AzaGly7, Arg(Me)9] MS10 1.0E-07 236 [D-Tyr1, D-Trp3, AzaGly7, Arg(Me)9] MS10 4.2E-08 237 [D-Tyr1, D-Asn2, AzaGly7, Arg(Me)9] MS10 2.7E-08 238 [D-Tyr1, D-Asn2, D-Trp3, AzaGly7, Arg(Me)9] MS10 4.9E-08 239 des(1)-[D-Tyr2, Ser3, AzaGly7, Arg(Me)9] MS10   1.2E-07 240 des(1)-[D-Tyr2, Ile3, AzaGly7, Arg(Me)9] MS10 1.7E-08 241 des(1)-[D-Tyr2, Thr3, AzaGly7, Arg(Me)9] MS10 5.6E-08 242 des(1)-[D-Tyr2, D-Trp3, AzaGly7, Arg(Me)9] MS10 7.0E-08 244 [D-Tyr1, Phe3, AzaGly7, Arg(Me)9] MS10 7.7E-08 245 [D-Tyr1, Nal(1)3, AzaGly7, Arg(Me)9] MS10 9.8E-08 246 [D-Tyr1, Nal(2)3, AzaGly7, Arg(Me)9] MS10 7.1E-09 247 [D-Tyr1, Phe(2Cl)3, AzaGly7, Arg(Me)9] MS10 4.5E-08 248 [D-Tyr1, Phe(3Cl)3, AzaGly7, Arg(Me)9] MS10 5.8E-08 249 [D-Tyr1, Phe(4Cl)3, AzaGly7, Arg(Me)9] MS10 1.5E-07 250 [D-Tyr1, Phe(4NH2)3, AzaGly7, Arg(Me)9] MS10 3.7E-09 251 [D-Tyr1, Pya(3)3, AzaGly7, Arg(Me)9] MS10 8.7E-08 252 [D-Tyr1, D-Ala3, AzaGly7, Arg(Me)9] MS10 5.8E-07 253 [D-Tyr1, Pro3, AzaGly7, Arg(Me)9] MS10 2.7E-08 254 des(1)-[D-Tyr2, Phe3, AzaGly7, Arg(Me)9] MS10 1.1E-08 255 des(1)-[D-Tyr2, Nal(2)3, AzaGly7, Arg(Me)9] MS10 3.3E-08 256 des(1)-[D-Pya(3)2, Phe3, AzaGly7, Arg(Me)9] MS10 2.2E-08 257 [D-Tyr1, D-Asn2, Phe3, AzaGly7, Arg(Me)9] MS10 4.0E-08 258 [D-Pya(3)1, AzaGly7, Arg(Me)9] MS10 9.0E-08 259 [D-Ala1, AzaGly7, Arg(Me)9] MS10 2.5E-07

[Table 17]

260 des(1-3)-3-(3-indolyl)propionyl-[AzaGly7, Arg(Me)9]MS10 3.2E-07 261 [7?8, CH2NH]MS10 3.9E-07 265 des(1-3)-indole-3-carboxy (carboxyl)-[AzaGly7, Arg(Me)9]MS10 9.5E-08 266 des(1-3)-indole-3-acetyl-[AzaGly7, Arg(Me)9]MS10 2.3E-07 267 des(1-3)-4-(3-indolyl)butanoyl-[AzaGly7, Arg(Me)9]MS10 3.6E-07 268 des(1-3)-Diphenylacetyl-[AzaGly7, Arg(Me)9]MS10 5.5E-07 269 des(1-3)-3-phenylpropionyl-[AzaGly7, Arg(Me)9]MS10 4.7E-07 270 Endo-Phe5a-[D-Tyr1, Phe3, AzaGly7, Arg(Me)9] MS10 1.5E-08 271 des(1-2)-[AzaGly7, Arg(Me)9]MS10   1.2E-07 272 des(1-2)-acetyl-[AzaGly7, Arg(Me)9]MS10 5.4E-07 273 des(1-2)-Amidino-[AzaGly7, Arg(Me)9]MS10 3.0E-07 275 des(1-2)-acetyl-[Arg3, AzaGly7, Arg(Me)9] MS10 4.1E-07 276 des(1-2)-acetyl-[Thr3, AzaGly7, Arg(Me)9] MS10 4.8E-07 277 des(1-3)-n-hexanoyl-[AzaGly7, Arg(Me)9]MS10 5.4E-08 278 des(1-3)-Cyclohexanecarbonyl-[AzaGly7, Arg(Me)9]MS10 1.1E-07 279 des(1-3)-2-(indol-3-yl)ethylcarbamoyl-[AzaGly7, Arg(Me)9]MS10 2.9E-08 281 [D-Tyr1, Pya(2)6, Arg(Me)9] MS10 2.3E-07 283 [D-Tyr1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10 6.9E-10 284 [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg(Me)9] MS10 3.4E-08 285 [D-Tyr1, Pya(2)3, AzaGly7, Arg(Me)9] MS10 4.0E-08 286 [D-Tyr1, Pya(4)3, AzaGly7, Arg(Me)9] MS10 1.7E-08 287 [D-Tyr1, D-Ser2, AzaGly7, Arg(Me)9] MS10 2.3E-09 288 [D-Tyr1, D-His2, AzaGly7, Arg(Me)9] MS10 7.2E-11 289 [D-Pya(3)2, AzaGly7, Arg(Me)9] MS10-(2-10) 8.4E-09 290 [D-Pya(3)1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10 1.4E-09 291 [D-Pya(3)1, D-Tyr2, Cha3, AzaGly7, Arg(Me)9] MS10 4.1E-10 294 [1?2,CH2NH]MS10 3.0E-08 295 [2?3,CH2NH]MS10 6.8E-07 296 [6?7, CSNH, D-Tyr1, Arg(Me)9] MS10   1.4E-08 297 [D-Tyr1, Thr5, AzaGly7, Arg(Me)9] MS10 9.3E-10 298 [D-Tyr1, D-Asn2, Thr5, AzaGly7, Arg(Me)9] MS10 2.5E-10 299 [1ψ2, CH2NH, AzaGly7, Arg(Me)9]-MS10 1.2E-09 300 [1ψ2, CH2NH, D-Trp3, AzaGly7, Arg(Me)9]-MS10 3.8E-09 301 [D-Tyr1, Ala(2-Qui)3, AzaGly7, Arg(Me)9] MS10 1.5E-08

[Table 18]

302 [D-Tyr1, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10 7.7E-09 303 [D-Tyr1, D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9] MS10 5.0E-10 304 [D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9] MS10 5.0E-09 305 des(1)-[D-Tyr2, D-Pya(4)3, AzaGly7, Arg(Me)9] MS10 1.3E-09 306 [D-Pya(4)1, D-Asn2, Cha3, AzaGly7, Arg(Me)9] MS10 4.4E-09 307 [7ψ8, CH2NH, D-Tyr1, Arg(Me)9] MS10 6.4E-08 308 [6ψ7, CH2NH, D-Tyr1, Arg(Me)9] MS10 3.5E-07 310 [Nar9] MS10 3.1E-07 311 [Nar(Me)9]MS10 4.7E-07 312 [Har(Me)9]MS10 1.0E-07 313 [Dab9] MS10 6.9E-07 314 [Orn9] MS10 4.7E-07 316 [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg(Me)9, Phe(4F)10] MS10 2.6E-08 317 [D-Tyr1, D-Asn2, Pya(4)3, AzaGly7, Arg(Me)9, Phe(4F)10] MS10 2.1E-09 318 [D-Tyr1, AzaGly7, Arg(Me)9, Phe(4F)10] MS10 9.9E-10 319 [6ψ7, NHCO, D-Tyr1, Arg(Me)9] MS10 9.7E-09 322 des(1-3)-3-pyridylpropionyl-[AzaGly7, Arg(Me)9]MS10 5.4E-08 323 des(1-3)-4-imidazoleacetyl-[AzaGly7, Arg(Me)9]MS10 2.8E-07 328 des(1-3)-D-glucuronide-[AzaGly7, Arg(Me)9]MS10 4.7E-07

Test Example 2

Activity of increasing intracellular Ca ion levels measured using FLIPR

According to the method described in Japanese Patent JPA2000-312590, the activity of increasing intracellular Ca ion level was measured using FLIPR.

The stable expression cell line rOT7T175 was obtained by using the CellPhect transfection kit (AmershamPharmacia Biotech Company) to transduce the animal cell expression plasmid pAK-rOT175 into CHO/dhfr- cells. First, 240 µL of buffer A (supplied in the CellPhect Transfection Kit) was added to 9.6 µg of plasmid DNA dissolved in 240 µL of distilled water, followed by stirring. After the mixture was allowed to stand for 10 minutes, 480 µL of buffer B (supplied with the CellPhect Transduction Kit) was added to the mixture, and vigorously stirred to form liposomes containing the DNA. Afterwards, 4×10 ⁵ CHO/dhfr ^- cells (obtained from ATCC) were seeded in 60 mm Petri dishes. After culturing it in Ham's F-12 culture solution (Nissui Seiyaku Company) containing 10% fetal bovine serum (BIO WHITTAKER Company) at 37° C. under the condition of 5% carbon dioxide gas for 2 days, 480 μ L of liposomes were added dropwise to the skin. on cells in a Petri dish. After incubating the cells at 37°C under 5% carbon dioxide gas for 6 hours, the cells were washed twice with serum-free Ham's F-12 medium, and 3 μL of 15% glycerol was added to the cells in the petri dish. The treatment was carried out for 2 minutes. The cells were again washed twice with serum-free Ham's F-12 medium, and then cultured in Ham's F-12 medium containing 10% fetal calf serum for 15 hours at 37°C under 5% carbon dioxide gas. Cells were dispersed by trypsinization and recovered from the petri dish. The recovered cells were seeded in a 6-well plate at a concentration of 1.25×10 ⁴ cells/well, and cultured in Dulbecco's modified Eagle medium (DMEM medium) containing 10% dialyzed fetal bovine serum (JRH BIOSCIENCES Company) ( Nissui Seiyaku Co., Ltd.) at 37° C. under the condition of 5% carbon dioxide gas. Transformed CHO cells transfected with the plasmid grew in culture, but non-transfected cells gradually died. Change medium daily or every 2 days to remove dead cells. Approximately 20 clones of transformed CHO cells grown to 8 to 10 days after culture were isolated. From these cloned cells, cells having high activity against the ligand peptidyltransferin (hereinafter, abbreviated as hOT7T175/CHO) were selected for the following experiments.

For the synthetic peptides, the intracellular Ca ion level increasing activity in hOT7T175/CHO was measured using FLIPR (Molecular Devices).

hOT7T175/CHO was subcultured in DMEM (hereinafter referred to as 10% dFBS/DMEM) supplemented with 10% dialyzed fetal bovine serum (hereinafter referred to as dFBS) for the experiment. Suspend hOT7T175/CHO at a concentration of 15× ¹⁰ cells/ml in 10% dFBS-DMEM, and inoculate 200 μl (3.0×10 ⁴ cells/200 μl) of the suspension, and then cultured overnight at 37° C. in a 5% CO ₂ incubator. The cells thus cultured were used for experiments (hereinafter, simply referred to as cell plates). 21 ml of HANKS/HBSS (after adjusting the pH of a mixture of 9.8 g of HANKS', 0.35 g of sodium bicarbonate, and 20 ml of 1M HEPES to 7.4 with 1N sodium hydroxide, the mixture was sterilized by filtration), 210 μl 250 mM probenecid and 210 μl fetal bovine serum (FBS) (HANKS/HBSS-probenecid-FBS) were mixed.

Separately, 2 vials of Fluo3-AM (50 μg/vial) were dissolved in 21 μL of dimethylsulfoxide and 21 μL of 20% pluronic acid. The resulting solution was added to the above 10 ml of HANKS/HBSS-probenecid-FBS and mixed. After removing the culture medium, the mixed solution was added to the cell plate in an amount of 100 µl per well, followed by incubation in a 5% CO ₂ incubator at 37° C. for 1 hour (pigment loading). The peptide was dissolved in dimethylsulfoxide at a concentration of 1×10 ^-3 M. The peptide solution was diluted with HANKS'/HBSS containing 2.5 mM probenecid and 0.2% BSA. This dilution was transferred to a 96-well plate for FLIPR (V-bottom plate, Coster Co.) (hereinafter referred to as a sample plate). After the pigment loading on the cell plate was finished, the cell plate was washed 4 times with wash buffer using a plate washer, leaving 100 μL of wash buffer obtained by adding 2.5 mM probenecid to HANKS'/HBSS. The cell plate and sample plate are placed in the FLIPR, and the 0.05ml sample is automatically transferred from the sample plate to the cell plate through the FLIPR device to accelerate the cell response. Changes in intracellular calcium ion levels were measured over a period of 180 seconds.

In Tables 19 to 23, the activity [specific activity relative to transferin (1-54)] of increasing intracellular Ca ion level is shown.

[Table 19]

Compound No. Specific activity Transferin (1-54) 1 Transferin (45-54) 10 17 5 18 1 19 2 twenty four 1 30 10 31 2 32 10 40 30 41 10 42 30 45 1 50 30 53 1 54 5 55 5 56 1 74 1 75 1 76 1 78 10 79 1 87 1 86 1 97 10 98 1/2 101 10 105 1 109 20 110 20 111 3 112 2 114 3 128 10 130 10 131 3 132 10 133 3 134 30 141 10 142 2 143 3 144 1 146 10 151 1 152 5 154 5 156 2 163 1 166 5 169 2 170 1 171 10 172 1 173 1

[Table 20]

174 10 176 5 182 5 187 1 189 10 190 10 192 1 193 1/2 194 1 197 10 198 10 199 3 200 10 201 1 203 10 204 5 205 10 206 10 207 1/2 208 1 209 1/2 210 1 211 10 212 10 213 2 214 10 215 10 216 1 217 20 220 5 222 10 224 2 225 1 226 1 227 1 228 5 229 1 230 10 231 1 232 3 233 1 234 1 235 1 236 2 237 3 238 1 241 1 242 2 244 1 245 1 246 2 247 1 248 2 249 1 250 1 254 1 255 1

[Table 21]

256 1 257 3 258 2 259 1 260 5 261 1 265 3 266 2 267 2 268 1 269 3 270 1 271 1 272 2 273 5 274 1 277 2 278 2 279 5 281 1/2 284 1 286 2 287 2 288 1 289 1 290 1 291 2 294 10 295 1 296 3 297 1 298 5 299 5 300 5 301 1 302 2 303 5 304 3 305 5 306 2 307 1 308 2 310 3 311 1 312 3 314 1 315 1 316 1 317 1 318 5 319 3 322 1 323 1 332 2 333 1 334 5 339 2

[Table 22]

340 1/5 341 2 344 1/2 345 2 346 2 347 1/2 348 1/5 349 1/5 351 1/2 352 1/3 353 10 354 10 358 2 362 1/10 364 1 366 1/3 367 1/5 368 1/2 369 2 373 2 374 1/3 375 2 378 1/2 379 2 380 5 385 10 386 7 387 1 392 1/5 393 1 397 5 400 1 408 1/3 412 1/5 417 1 421 1/3 423 5 428 1/10 431 1 432 2 434 1/10 435 10 436 5 437 2 438 3 439 2 440 1 441 1 442 1/2 443 1/2 444 1/3 445 5 446 1 447 5 448 3 449 5 450 1/3

[Table 23]

451 5 452 1 453 1 454 6 455 5 459 2 460 1/3 461 1/3 462 1 463 2 464 1 466 1/3 467 1 468 1 471 1 472 3 473 3 474 5 475 3 477 1/5 478 1/3 479 5 480 1 481 5 486 1/2 487 1 488 1 489 1/2 490 3 491 7 492 5 493 2 494 1/3 495 1/6 496 5 497 2 498 7 499 10 500 1 501 10 502 10 503 10 504 2 505 20 506 1 507 5 508 10 509 20 510 3 511 10 512 30 513 20 514 10 515 10

Test Example 3

Activity of increasing intracellular Ca ion levels measured using FLIPR

As in Test Example 2, the activity of increasing the intracellular Ca ion level was measured using FLIPR. However, (1) the method of evaluating the change in the intracellular Ca ion level in the immediate measurement period of 180 seconds in Test Example 2 was changed to evaluating the situation at 40 seconds after the start of the reaction. And (2) changing the expression of activity from the specific activity relative to transferin (1-54) to the _EC50 /MS10 _EC50 value. Some evaluation results are shown in Table 24.

[Table 24]

Compound number specific activity 40 1.6 41 2.7 42 1.6 82 1.0 97 2.9 109 2.6 114 4.1 128 0.5 134 0.5 141 1.6 116 1.5 152 1.4 156 0.9 174 2.3 176 1.3 187 1.9 206 4.8 208 7.3 210 9.3 211 1.3 212 1.1 217 3.1 222 2.7 232 3.9 239 6.7 240 4.9 241 5.3 242 1.4 260 4.3 265 4.4 266 6.4

268 4.5 269 3.4 279 6.4 294 0.7 296 5.2 297 5.5 298 1.8 303 6.9 305 2.0 308 2.6 310 2.0 311 6.2 312 4.0 314 4.4 318 2.9 319 3.1 322 5.4 332 4.9 333 5.0 334 1.4 339 5.9 341 2.8 353 0.8 354 0.8 358 5.6 369 4.8 375 5.2 378 10.4 379 3.0 385 0.7 386 2.9 387 5.0 393 5.9 423 5.6

436 1.4 438 3.0 445 4.2 447 1.4 449 4.2 451 2.6 454 2.5 455 4.1 459 7.3 463 4.6 464 10.5 467 4.0 468 5.2 472 3.4 473 4.2 474 3.2 475 4.2 479 2.6 480 8.3 481 2.4 488 5.5 490 6.2 491 1.0 492 1.1 493 2.2 494 8.6 496 0.7 497 1.4 498 1.5 499 1.4 500 3.2 501 1.1 502 1.4 503 0.4

504 6.9 505 0.7 506 1.3 507 1.7 508 1.0 509 2.0 510 3.5 511 0.5 512 0.8 513 0.4 514 0.7 515 1.0 516 3.7 517 1.0 518 10.5 519 2.4 521 2.4 522 1.9 523 1.1 524 1.1 527 3.3 528 1.4 529 1.8 530 3.4 531 1.8 532 1.0 533 9.7 534 5.6 535 0.8 536 1.8 537 4.7 538 3.3 539 1.2 540 0.7

541 2.0 542 1.4 545 1.1 546 1.9 547 2.5 548 1.7 550 0.7 551 1.2 552 2.3 553 1.9 554 1.3 555 1.5 556 2.8 557 3.2 558 0.4 559 0.3 561 1.6 562 1.0 563 0.7 564 0.5 565 0.6 566 0.8 567 0.8 568 0.6 569 0.5 570 0.5 571 1.2 572 0.7 573 0.7 576 0.8 577 0.7 578 0.8 579 0.6 580 0.6

Compound No. Specific activity 584 0.4 585 0.4 586 0.3 589 2.3 590 1.4 591 1.2 592 1.1 594 2.1 595 11.4 597 0.6 598 0.3 599 0.5 600 0.3 601 3.1 602 2.4 603 1.7 604 6.3 605 3.9 607 2.2 608 2.2 609 0.9 610 1.9 611 1.7 812 0.8 613 0.4 614 0.8 615 0.7 616 1.1 617 2.4 618 1.6 619 1.5 620 1.7 621 1.9 622 2.8 623 0.8 624 1.2 625 2.8 626 2.1 627 1.6 628 4.4 629 3.4 630 4.2 631 2 632 1.1 633 3.4 634 10.5 635 1.4 637 0.8 638 1.7 639 2 641 3.5 642 3.7 643 2.5 644 2.5 645 1.1 646 1.8

647 10.6 648 1.6 649 1 650 0.6 651 0.7 652 0.9 653 1.3 654 2.9 655 4.7 656 2.9 657 1.1 658 0.4 659 0.6 660 1.1 661 8.5 662 0.7 663 0.8 664 0.6 665 1.1 666 1.1 667 1.4 668 1.2 669 0.5 670 0.9 671 3.6 672 2.1 674 2 675 0.8 676 1.4 677 0.3 678 1.1 679 1.8 680 2.5 681 1.2 682 7.3 685 4.8 686 0.6 688 9.7 689 2.3 691 1.1 692 0.7 693 1.5 694 1.7 695 0.7 696 0.5 698 2.2 699 1.3 700 0.8 701 1.4 702 0.6 703 3.7

Test Example 4

Determination of the cytostatic activity of hOT7T175-expressing CHO cells

hOT7T175-expressing CHO cells (hereinafter referred to as hOT7T175) were cultured in DMEM supplemented with 10% dialyzed FBS (hereinafter referred to as 10% dFBS/DMEM) and used for the following measurements. hOT7T175 was suspended in 10% dFBS/DMEM at a concentration of 10000 cells/ml. Cells were inoculated in a 96-well plate at a concentration of 100 μL/well (1000 cells/well), and cultured overnight in a 37° C.-5% CO ₂ incubator. The next day, the medium was removed, and 90 μL of 10% dFBS/DMEM supplemented with 0.5% BSA (hereinafter referred to as 0.5% BSA/10% dFBS/DMEM) was added. Next, 10 μL of transferin or transferin derivative solution dissolved in 0.5% BSA/10% dFBS/DMEM was added to each well, and then cultured in a 37° C.-5% CO ₂ incubator for 3 days. After adding 10 μL of Counting Kit-8 solution (Dojin Chemical Laboratory) to each well, the cells were cultured in a 37° C.-5% CO ₂ incubator for 4 hours, and the absorbance was measured at 450 nm.

The cytostatic activities of transferins (1-54), transferins (45-54) and synthetic compounds are shown in Table 25.

[Table 25]

Compound No. IC50(M) 305 8.94E-09 232 9.67E-09 286 1.83E-08 303 4.12E-08 322 7.19E-08 141 8.70E-08 1-54 2.12E-07 45-54 8.51E-06

*"1-54" and "45-54" represent transferin (1-54) and transferin (45-54), respectively.

Test Example 5

Determination of Chemotaxis Inhibitory Activity of hOT7T175-expressing CHO Cells

hOT7T175-expressing CHO cells (hereinafter referred to as hOT7T175) were cultured in DMEM supplemented with 10% dialyzed FBS (hereinafter referred to as 10% dFBS/DMEM) and used for experiments. A 24-well 6.5 mm Transwell (pore size 8.0 μm) (COSTAR) was treated with fibronectin by the following method. Specifically, 0.5 ml of 1 µg/ml bovine fibronectin (Yagai Co., Ltd.) was added to the upper and lower chambers of the Transwell. After the mixture was left at room temperature for 10 minutes, the fibronectin solution was removed and air-dried. hOT7T1753 was washed with DMEM three times, and the cells were suspended in DMEM supplemented with 0.5% BSA (hereinafter referred to as 0.5% BSA/DMEM) at a density of 2.5×10 ⁶ cells/ml. Transferin or transferin derivatives were diluted with 0.5% BSA/DMEM. After adding 600 μL of 0.5% BSA/DMEM supplemented with 20% FBS (or 0.5% BSA/DMEM for negative control) to the lower chamber of the Transwell, add 50 μL of cell suspension and 50 μL of transferin or transferin to the upper chamber. Dilution solution of prime derivatives (or for positive control, add 0.5% BSA/DMEM). After culturing at 37°C for 7 hours in a 5% CO ₂ incubator, the culture medium was removed, and all cells on the upper surface of the filter were removed by wiping the upper surface of the filter with a cotton swab moistened with phosphate-buffered saline. The filter was fixed, stained with DifQuick (International Reagents Corporation), and the cells migrating to the lower surface of the filter were counted. Chemotaxis inhibitory activity is shown in FIG. 1 .

Test Example 6

Evaluation of Tumor Growth Inhibitory Activity

Using mice bearing the human colon cancer cell line SW620, the tumor growth inhibitory activities of metastasin (1-54) (hereinafter referred to as metastasin) and compounds (compound Nos. 305 and 322) were evaluated.

Alza osmotic pumps (0.25 μL/hour, release for 14 days, type 1002) were subcutaneously implanted into the back of BALB/cAnN-nu mice (6-week-old, female, Charles River Japan, Inc.) under ether anesthesia. For a 14-day dosing cycle, Alza osmotic pumps were filled with 100 μL of 1 mM transferin, 0.1 mM and 1 mM compounds dissolved in distilled water (Otsuka Joryusui KK), and 100 μL of distilled water as a vehicle, respectively. The number n of experimental cases in the transferin group and the vehicle group was 10, and n was 11 in the compound group. The next day, human colon cancer cell line SW620 (ATCC) was dissolved in 200 μL of 20 mM phosphate buffered saline (pH 7.2) (PBS) containing 0.15 M NaCl at a density of 2×10 ⁶ cells. The resulting solution was subcutaneously injected into the left flank of the above mice. The date of inoculation of cells is referred to as day 0. From the 4th day to the 13th day after cell inoculation, the tumor was measured with an electronic caliper every day or every other day, and the size of the tumor was calculated using the following formula: (short diameter) ² × long diameter/2. As shown in Figure 2, compared with the vehicle, the transferin group (24 nmol/day/mouse×14 days) showed a significant tumor growth inhibitory effect on the 6th day. On the other hand, the compound No. 322 group showed significant tumor growth inhibitory activity on days 6 to 8 at a dose 1/10 of that of transferrin (2.4 nmol/day/mouse×14 days). In addition, compared with the vehicle group, the compound No. 322 group (24 nmol/day/mouse × 14 days) at the same dose as transferrin showed significant tumor growth inhibitory activity from day 6 to day 11, and on day 11 , showed significant tumor growth inhibitory activity even compared with the transferin group. From the above results, it can be seen that transferin also exhibits tumor growth inhibitory effect in vivo, and compound No. 322 has a tumor growth inhibitory effect 10 times higher than transferin.

The results for Compound No. 305 are also shown in FIG. 3 . Compared with the vehicle group, the transferin group (24 nmol/day/mouse×14 days) showed a significant tumor growth inhibitory effect from the 5th day to the 7th day. On the other hand, compared with the vehicle group, the compound number 305 group (2.4nmol/day/mouse×14days) showed significant tumor growth on the 5th to the 11th day at a dose equivalent to transferrin 1/10 inhibitory activity. In addition, compared with the vehicle group, the compound number 305 group (24nmol/day/mouse×14days) at the same dose as transferrin showed significant tumor growth inhibitory activity on the 5th to the 9th day and on the 11th day , from the above results, it can be seen that compound No. 305 has a tumor growth inhibitory effect 10 times higher than that of transferrin.

Test Example 7

Sugar-Level-Elevating Effects of Transferins

To study the effect of peripherally administered transferrin on increasing glucose levels, blood was surgically collected from freely moving animals. Adult Wistar male rats (210-230 g body weight at the time of surgery) were anesthetized by intraperitoneal injection of 50 mg/kg pentobarbital. Mount the animal dorsally on a dissecting table and expose the left jugular vein. A polyethylene tubule SP35 (inner diameter 0.5 mm, outer diameter 0.9 mm, Natsume Seisakusho Co., Ltd.) was cut to a length of about 30 cm, and filled with 200 units/ml of physiological saline containing heparin. Thereafter, the cannula was inserted into the jugular vein to a depth of approximately 4.5 cm and secured. The other end of the tubule passes under the skin on the dorsal side and emerges from the neck (dorsal side).

After surgery, babysitting the animals overnight. Before the transferin administration, 300 µl of blood was drawn using a 1 ml tuberculin syringe and a 25-gauge injection needle (both from Terumo Co., Ltd.). To prevent blood coagulation, inject 3 μl of 300 KIU/ml aprotinin containing 3 mg/ml EDTA into the syringe beforehand. 1 mL (17, 80 or 170 nmol) of Otsuka's normal saline or transferin's normal saline solution was injected intravenously through a cannula at a dose of 1 mL/kg. At each time point of 0, 5, 15, 30 and 60 minutes from the intravenous injection, 300 μl of blood was collected from the jugular vein. The collected blood samples were centrifuged (13000 rpm, 5 minutes) with a high-speed refrigerated centrifuge (MR-150, Tomy Seiko Co., Ltd.), and the supernatant (plasma) was recovered. Blood glucose levels were measured using Fujidrychem 3500 (FUJI FILM). As shown in Figure 4, compared with the control group, the transferin group started 5 minutes after the intravenous injection, and showed a significant effect (p＜0.005, n=5) on improving the glucose level in the blood, and had a dose-dependent ( 17-170nmol/kg). It can be confirmed that the glucose level in the blood increases with the increase of the dose of transferin, which can show the increase of the maximum value and the prolongation of the rising time (up to 30 minutes).

Test Example 8

Glucagon secretion-promoting effect of transferin

In order to investigate the mechanism by which transferins increase blood glucose levels, the effects of transferins on blood levels of glucagon, insulin, corticosterone, and thyroid hormone (T3), which are hormones that change blood glucose levels, were studied. Blood was collected surgically from freely moving adult Wistar male rats (260-300 g body weight at the time of surgery). After surgery, babysitting the animals overnight. Before administration of transferin, 300 μl of blood was drawn using a 1 ml tuberculin syringe and a 25-gauge injection needle (both from Terumo Co., Ltd.). In order to prevent blood coagulation, 3 µl of 300 KIU/ml aprotinin containing 3 mg/ml EDTA was previously injected into the syringe. A normal saline solution (80 nmol) of Otsuka or transferin was intravenously injected through a small tube at a dose of 1 mL/kg. At each time point of 1, 3, 5, and 15 minutes from the intravenous injection, 300 µl of blood was collected from the jugular vein. The collected blood samples were centrifuged (13000 rpm, 5 minutes) with a high-speed refrigerated centrifuge (MR-150, Tomy Seiko Co., Ltd.), and the supernatant (plasma) was recovered. Blood glucagon levels were measured using a glucagon kit "Daiichi" (Daiichi Radioisotope Laboisoories Ltd.), blood insulin levels were measured using a rat insulin [ ¹²⁵ I] assay system (Amersham Biosciences), and rat corticosterone [ ¹²⁵ I] Determination System (Amersham Biosciences) was used to measure the level of corticosterone in blood, T-3.RIA beads (Dinabott Co. medium glucose levels. As shown in Fig. 5, compared with the control group, the transferin group showed a significant effect of increasing the blood glucagon level 1 minute after injection. This marked increase in blood glucagon levels lasted until 5 minutes after injection. On the other hand, blood insulin levels (Fig. 6), blood corticosterone levels (Fig. 7) and blood thyroid hormone (T3) levels (Fig. 8) did not change due to transferrin injection. Based on these results and the observed increase in blood glucose levels following the increase in blood glucagon levels (Fig. 9), it is considered that the effect of intravenous transferrin on increasing blood glucose levels may be due to transferin stimulation of the pancreas. caused by glucagon secretion.

Test Example 9

Sugar-level-increasing effect of transferin derivatives

The effects of transferin derivatives KiSS305 (Compound No. 305) and KiSS322 (Compound No. 322) on blood glucose levels and blood glucagon levels were investigated. In the same manner as in Test Example 1, free-moving adult Wistar male rats (body weight 260-300 g at the time of surgery) were operated on to collect blood. After surgery, babysitting the animals overnight. Before the transferin administration, 300 µl of blood was drawn using a 1 ml tuberculin syringe and a 25-gauge injection needle (both from Terumo Co., Ltd.). To prevent blood coagulation, inject 3 μl of 300 KIU/ml aprotinin containing 3 mg/ml EDTA into the syringe beforehand. Otsuka's normal saline or a transferin's normal saline solution (80 nmol) was intravenously injected through a small tube at a dose of 1 mL/kg. At each time point of 2, 5, 15, 30, 45 and 60 minutes from the intravenous injection, 300 μl of blood was collected from the jugular vein. The collected blood samples were centrifuged (13000 rpm, 5 minutes) with a high-speed refrigerated centrifuge (MR-150, Tomy Seiko Co., Ltd.), and the supernatant (plasma) was recovered. As in Test Example 1 or 2, blood glucose levels were measured using Fuji drychem 3500 (FUJI FILM), and blood glucagon levels were measured using a glucagon kit "Daiichi" (Daiichi Radioisotope Laboisoories Ltd.). As shown in Figure 10, the compounds all showed the effect of increasing blood glucose level. And as shown in Fig. 11, all the compounds showed the effect of increasing blood glucagon level.

Test Example 10

Ovulation induction of immature rats by human transferrin

Equine chorionic gonadotropin (eCG, serum gonadotropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in physiological saline (Otsuka Pharmaceutical Co., Ltd.) at a concentration of 100 IU/mL. Between 9:30 am and 10:00 am, eCG was injected subcutaneously at 10 IU per animal on the 23rd day using a 1 ml tuberculin syringe and a 26-gauge injection needle (both from Terumo Co., Ltd.). The back of a female Wistar rat (Charles River Japan, Inc.). After 47 to 48 hours of eCG injection, the patients were grouped according to the following method and administered separately.

Group A (5 rats): Human chorionic gonadotropin (hCG, gonadotropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in physiological saline at a concentration of 100 IU/mL, and the solution was used for each animal A dose of 20 IU is injected subcutaneously into the back.

Group B (5 rats): Human transferin was dissolved in physiological saline at a concentration of 100 nmol/mL, and the solution was subcutaneously injected into the back of each animal at a dose of 20 nmol.

Group C (5 rats): Human transferin was dissolved in physiological saline at a concentration of 33.3 nmol/mL, and the solution was subcutaneously injected into the back of each animal at a dose of 6.67 nmol.

Group D (6 rats): Physiological saline was subcutaneously injected into the back at a dose of 200 μL per animal.

24 to 25 hours after the end of the above-mentioned administration, the animals were sacrificed by decapitation, and blood, bilateral fallopian tubes and uterus were collected. When collecting blood, in order to prevent blood coagulation, 90 μl of 10 KIU/ml aprotinin solution (Trasylol, Bayer) containing 3 mg/ml EDTA was injected into the small tube in advance. After blood was collected, it was thoroughly mixed and centrifuged at 2000G for 25 minutes. After recovering the supernatant, it was used as a plasma sample.

Oocytes were counted as follows.

When the oviduct was observed under a stereomicroscope and the oviducal ampulla was found to be lodged, the oviducal ampulla was punctured with a syringe (Terumo) with a 27-gauge needle to remove the oviducal ampulla. Oocytes were counted after removing the granulosa cells surrounding the oocytes by trypsinization. When the oviduct was observed through a stereoscopic microscope and no oocytes were found to remain in the enlarged part of the oviduct, a syringe with a 27-gauge injection needle with a grounded head was inserted into the oviduct orifice, and more than 400 μL of normal saline was injected to wash the oviduct and the uterus. Afterwards, the presence or absence of oocytes in the effluent was observed.

The obtained ovulation numbers are shown in Table 26.

[Table 26]

Group A Group B Group C Group D 1 36 29 29 0 2 35 56 39 0 3 40 17 32 0 4 42 25 twenty two 0 5 35 32 16 0 average ovulation 37.6 31.8 27.6 0.00 standard deviation 3.21 14.65 8.91 0.00

In the table, "1" to "5" represent the number of each rat

In group A, which is a common hyperovulation treatment group, the average number of ovulations per rat was confirmed to be 37.6. In the transferin-administered groups B and C, the confirmed ovulation numbers were 31.8 and 27.6, respectively. For group D administered with physiological saline, the average number of ovulations was 0.6, which indicates that spontaneous ovulation under ovulation stimulation hardly existed.

The estradiol levels in the blood of the rats shown in Table 22 were measured by radioimmunoassay (DPC-estradiol kit; Diagnostic Products Corporation), and the results are shown in FIG. 12 .

The results showed that there was no difference in blood estradiol levels between groups A, B, and C, only group D given normal saline had very high estradiol levels.

The blood progesterone level was measured by radioimmunoassay (DPC.Progesterone; Diagnostic Products Corporation), and the results are shown in FIG. 13 .

The results showed that the progesterone level was the highest in group A, the blood progesterone levels in groups B and C were about half of those in group A, and the progesterone level in group D was very low.

Typically, the major steroid hormones produced in the ovaries of rats, mice, and humans are estrogen during follicular maturation and progesterone after ovulation induction. In fact, it is also clear from the results in Fig. 12 and Fig. 13 that the D group administered with normal saline maintained a high level of estrogen production because ovulation was not induced; while the estrogen production increased in the A group administered with hCG. In groups B and C given transferrin, the plasma estrogen level was very low, but the progesterone level was increased, which indicated that transferin induced ovarian ovulation in rats through the normal ovulation process. Also, since the progesterone levels in groups B and C were lower than in group A, transferins are thought to have a milder ovarian stimulating effect

Test Example 11

Effect of Human Transferin on Gonadotropin Release in Juvenile Rats

Between 9:00 am and 10:00 am, 33.3 nmol/mL human transferin in normal saline solution was injected subcutaneously to 25 The back of a day-old female rat (Charles River Japan, Inc.). Animals were decapitated before injection of transferin and 1, 2 and 4 hours after injection. To prevent blood coagulation, 90 μl of a 10 KIU/ml aprotinin solution (Trasylol, Bayer) containing 3 mg/ml EDTA was placed in a centrifuge tube before collecting the blood. After recovering the blood, the blood was thoroughly mixed, and the mixture was centrifuged at 2000G for 25 minutes. After recovering the supernatant, it was used as a plasma sample. By radioimmunoassay (rat follicle-stimulating hormone (rFSH) [ ¹²⁵ I] Biotrack assay system - magnetic separation, rat luteinizing hormone (rLH) [ ¹²⁵ I] Biotrack assay system - magnetic separation, both from Amersham Bioscience, DPC Progesterone was from Diagnostic Products Corporation), and the levels of FSH (follicle-stimulating hormone), LH (luteinizing hormone) and progesterone in plasma were measured.

The measurement results of FSH level changes in the blood of immature rats after transferrin injection are shown in FIG. 14 . One hour after transferrin injection, the level of FSH in the blood started to increase significantly and reached the maximum after 2 hours. After 4 hours, the level of FSH in the blood did not decrease, and the level of FSH was still higher than that before the injection.

Figure 15 shows the measurement results of changes in LH levels in the blood of immature rats after transferrin injection. As in the case of FSH, the level of LH in the blood starts to rise significantly after 1 hour and reaches the maximum after 2 hours. After 4 hours, the level of LH in the blood did not decrease, and the level of LH remained higher than that before the injection.

The measurement results of progesterone level changes in the blood of immature rats after transferrin injection are shown in FIG. 16 . Due to the influence of rising LH level in the blood, the progesterone level began to increase slowly 1 hour after the transferrin injection, and showed a state significantly higher than the pre-injection level.

From the results in Figure 14 and Figure 15, it can be known that peripheral administration of transferogen can induce the release of gonadotropins such as FSH and LH. The ovulation-inducing effect shown by transferin in Test Example 9 is considered to be produced by the above-mentioned gonadotropin release, especially LH release.

The ovulation-inducing effect shown in Test Example 9 was produced on rats administered with eCG, whereas this Test Example is the result obtained using untreated rats. eCG pretreatment is not required in the case of transferins showing gonadotropin-releasing effects.

The results in Figure 16 show that the release of gonadotropins produced by transferrin injection also transmits physiological stimuli to the ovaries, resulting in increased progesterone production.

Test Example 12

Effect of human transferrin on gonadotropin release in adult male rats.

Between 10:30 am and 11:30 am, inject 175 nmol/mL human transferrin in normal saline at a dose of 200 μL per animal, which is equivalent to 35 nmol human transferin, and inject subcutaneously until 11 weeks of age The back of male Wistar rats (Charles River Japan, Inc.). Animals were decapitated before injection of transferin and 1, 2 and 4 hours after injection. In order to prevent blood coagulation, 300 μl of 10 KIU/ml aprotinin solution (Trasylol, Bayer) containing 3 mg/ml EDTA was placed in a centrifuge tube before the blood was collected. After recovering the blood, the blood was thoroughly mixed, and the mixture was centrifuged at 2000G for 25 minutes. After recovering the supernatant, it was used as a plasma sample. By radioimmunoassay (rat follicle-stimulating hormone (rFSH) [ ¹²⁵ I] Biotrack assay system - magnetic separation, rat luteinizing hormone (rLH) [ ¹²⁵ I] Biotrack assay system - magnetic separation, both from Amersham Bioscience, DPC Total testosterone was from Diagnostic Products Corporation), and the levels of FSH (follicle-stimulating hormone), LH (luteinizing hormone) and testosterone in plasma were determined.

Figure 17 shows the measurement results of changes in FSH levels in rat blood after transferin injection. One hour after transferrin injection, the level of FSH in the blood started to increase significantly and reached the maximum after 2 hours. After 4 hours, it still maintained a high state.

Figure 18 shows the measurement results of changes in LH levels in rat blood after transferrin injection. As in the case of FSH, the level of LH in the blood starts to rise significantly after 1 hour and reaches the maximum after 2 hours. After 4 hours, the level of LH in the blood did not decrease, and the level of LH remained higher than that before the injection.

The measurement results of the testosterone level changes in rat blood after transferin injection are shown in FIG. 19 . Testosterone levels rose rapidly 1 hour after transferrin injection. After 2 and 4 hours, no decrease in blood testosterone levels was seen, and the testosterone levels remained higher than the pre-injection levels at these two time points.

From the results in Figure 17 and Figure 18, it can be known that peripheral administration of transferogen can induce the release of gonadotropins such as FSH and LH in male rats. Considering the results of Test Example 10, it is considered that transferin is an extremely important factor for stimulating the release of gonadotropins for both females and males.

The results in Figure 19 show that the release of gonadotropins produced by the injection of transferrin also transmits a physiological stimulus to the testes, resulting in increased testosterone production.

From these results, it is known that the administration of transferrin stimulates the testis through the release of gonadotropins. This suggests that transferin may also affect male reproductive functions such as sperm maturation and hormone secretion.

Test Example 13

Blood Stability Test of Compounds

Blood was collected from 8-week-old (female) Balb/c mice, and the blood samples were placed at 37° C. for 30 minutes and centrifuged at 13000 rpm for 10 minutes to obtain mouse serum. The resulting serum was stored frozen at -80°C.

The stability test was carried out by adding 5 nmol of the compound (5 μL aqueous solution) to 45 μL serum, and then placing the mixture at 37°C. The standing time was 3 time points including 2, 10 and 30 minutes. After the standing samples were boiled for 3 minutes, they were cooled in an ice bath. After adding 200 μL of acetonitrile/water (3/1) to the sample, the mixture was sonicated for 5 minutes and centrifuged at 5000 rpm for 1 minute. After diluting 150 μL of the supernatant with 250 μL of distilled water, the insoluble matter was filtered through a filter with a pore size of 0.45 μm, and 200 μL of the filtrate was analyzed by HPLC (220 nm) to obtain the peak area of the compound. The ratio of the peak area to the area when the compound was treated for 0 minutes under the same conditions was calculated as the average value of each of four repetitions, and the residual rate was obtained. Next, when plotting the obtained residual rate on the vertical axis and time on the horizontal axis, it approximated an exponential function. Calculate the time when the residual rate is 50%, and this time is the half-life.

LC-VP series manufactured by Shimadzu was used as the preparative HPLC, and Wakosil-II 5C18 HG (4.6 mm×100 mm) manufactured by Wako Pure Chemical Industries, Ltd. was used as the column. As eluents, eluent A (0.1% TFA-water) and eluent B (0.1% TFA-acetonitrile) were used. With a flow rate of 1.0ml/min, use eluent A/B: 100/0-0/50 for linear concentration gradient elution (25 minutes)

The compounds used in the test and their t _1/2 (min) values are shown in Table 27.

[Table 27]

Compound number t _1/2 (min) 1 22.5 3 0.6 42 0.7 82 1.8 134 2.4 141 8.7 232 28.2 286 57.5 296 47.2 305 66.6 308 13.2 319 33.0 322 94.2

Test Example 14

Ovulation induction of immature rats by transferin derivatives

Equine chorionic gonadotropin (eCG, serum gonadotropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in physiological saline (Otsuka Pharmaceutical Co., Ltd.) at a concentration of 100 IU/mL. Between 9:30 am and 10:00 am, eCG was injected subcutaneously at 10 IU per animal on the 23rd day using a 1 ml tuberculin syringe and a 26-gauge injection needle (both from Terumo Co., Ltd.). The back of a female Wistar rat (Charles River Japan, Inc.). After 47 to 48 hours of eCG injection, the patients were grouped according to the following method and administered separately.

Group A (5 rats): Human chorionic gonadotropin (hCG, gonadotropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in physiological saline at a concentration of 100 IU/mL, and the solution was used for each animal A dose of 20 IU is injected subcutaneously into the back.

Group B (5 rats): the compound No. 305 was dissolved in physiological saline at a concentration of 33.3 nmol/mL, and the solution was subcutaneously injected into the back of each animal at a dose of 6.7 nmol.

Group C (5 rats): Compound No. 305 was dissolved in physiological saline at a concentration of 10.0 nmol/mL, and the solution was subcutaneously injected into the back of each animal at a dose of 2.0 nmol.

Group D (5 rats): the compound No. 322 was dissolved in physiological saline at a concentration of 33.3 nmol/mL, and the solution was subcutaneously injected into the back of each animal at a dose of 6.7 nmol.

Group E (5 rats): the compound No. 322 was dissolved in physiological saline at a concentration of 10.0 nmol/mL, and the solution was subcutaneously injected into the back of each animal at a dose of 2.0 nmol.

Group F (6 rats): Physiological saline was subcutaneously injected into the back at a dose of 200 μL per animal.

24 to 25 hours after the end of the above-mentioned administration, the animals were sacrificed by decapitation, and blood, bilateral fallopian tubes and uterus were collected. When collecting blood, in order to prevent blood coagulation, 90 μl of 10 KIU/ml aprotinin solution (Trasylol, Bayer) containing 3 mg/ml EDTA was injected into the small tube in advance. After blood was collected, it was thoroughly mixed and centrifuged at 2000G for 25 minutes. After recovering the supernatant, it was used as a plasma sample.

Oocytes were counted according to the method described in Eur. J. Endocrinol., 138, 594-600 (1998).

When the oviduct was observed under a stereomicroscope and oocytes were found to be lodged in the dilated part of the fallopian tube, the dilated part was punctured with a syringe (Terumo) with a 27-gauge needle to remove the oocyte. Oocytes were counted after removing the granulosa cells surrounding the oocytes by trypsinization. When the oviduct was observed through a stereoscopic microscope and no oocytes were found to remain in the enlarged part of the oviduct, a syringe with a 27-gauge injection needle with a grounded head was inserted into the oviduct orifice, and more than 400 μL of normal saline was injected to wash the oviduct and the uterus. Afterwards, the presence or absence of oocytes in the effluent was observed.

The obtained ovulation numbers are shown in Table 20. In group A, which is a common hyperovulation treatment group, the average number of ovulations per rat was confirmed to be 38.0. In groups B, C, and D, the average number of ovulations was confirmed to be 32.6, 29.4, and 29.6, respectively, and the ovulations in these groups were almost equivalent to those in group A. For Group E administered with 2.0 nmol of the compound No. 322, 3 out of 5 rats ovulated, and the average number of ovulations was 11.6, which was less than that of Group A. In addition, the absence of ovulation was confirmed for group A as a negative control.

From the results in Fig. 20, it can be known that in order to achieve ovulation induction equivalent to that of hCG, at least 2.0 nmol of compound No. 305 and at least 6.7 nmol of compound No. 322 should be administered per animal.

The measurement results of the plasma estradiol level are shown in Fig. 21 . Blood estradiol levels were determined by radioimmunoassay (DPC-estradiol kit, Iatron, Inc.). As shown in FIG. 21 , for estradiol, there was no significant difference among groups A, B, C, and D, and only group F showed a high value. In group E, rats without induction of ovulation tended to show high values.

The measurement results of progesterone levels in plasma are shown in FIG. 22 . Blood progesterone levels were measured by radioimmunoassay (DPC. Progesterone; Iatron, Inc.). As shown in Figure 22, the blood progesterone level in group A was the highest, and the progesterone levels in groups B, C and D were less than half of the level in group A. Groups E and F showed very low levels.

It can be seen from Figure 21 and Figure 22 that administration of more than 2.0 nmol of compound number 305 and more than 6.7 nmol of compound number 322 per animal can induce normal differentiation from estrogen-producing granulosa cells to progesterone-producing luteal cells . In addition, since progesterone levels were lower when Compound No. 305 or KiSS-322 was administered than when hCG was administered, it was suggested that these derivatives are less ovary stimulating than hCG.

Test Example 15

Evaluation of the Effect of Transferin Peptide Derivatives on Lowering Blood Testosterone Levels Using Adult Male Rats

A transferin peptide derivative (hereinafter, referred to as peptide) was dissolved in distilled water (Otsuka Joryusui K.K.) to prepare a 2 mM peptide solution. The peptide solution was filled into 5 ALZET osmotic pumps (Model 2001, 0.2 ml volume, release rate 0.001 ml/hr, DUREECT Corporation). ALZET pumps filled with the peptide solution were implanted subcutaneously in the back of five CD(SD)IGS male 9-week-old rats (Charles RiverJapan, Inc.), one each, under ether anesthesia. As a negative control, five ALZET osmotic pumps filled with distilled water (Otsuka Pharmaceutical Co., Ltd.) were implanted into five male CD(SD) IGS rats (Charles River Japan, Inc.) in the same manner. . The pump-transplanted rats were fed for 6 days under the usual feeding conditions. After weighing, the animals were decapitated and blood samples were taken. After adding 0.03 ml of aprotinin solution (Trasylol, Bayer) containing 0.1 mg/ml EDTA 2Na per 1 ml of blood, the mixture was centrifuged at 1800 G for 25 minutes to separate/recover plasma. Using 0.05 ml of the resulting plasma, the plasma testosterone level of each rat was measured by radioimmunoassay (DPC. Total Testosterone Kit, Diagnostic Products Corporation). Values below the detection limit of the radioimmunoassay (plasma concentration 0.04 ng/ml) were scored as 0. The average value of the testosterone levels of the 5 rats administered with the peptide was calculated, and the relative value (percentage) of this average value to the average value of the 5 rats administered with distilled water was calculated.

Various peptides were evaluated using this evaluation method, and some results are shown in Tables 28 and 29.

[Table 28]

Compound No. Blood testosterone (teststerone) level 334354436269386499305385492496134141176 40% 43% 35% 7% 23% 2% 2% 2% 65% 3% 50% 31% 12%

[Table 29]

Compound number blood testosterone levels 505 40% 508 9% 509 2% 512 2% 515 2% 517 79%

Test Example 16

Evaluation was performed in the same manner as in Test Example 14 using a 0.1 mM peptide solution, and some results are shown in Table 30.

[Table 30]

Compound number   Testosterone levels in the blood 305 48% 385 33% 499 32% 512 38% 516 3% 523 72% 538 45% 540 55% 545 37% 547 65% 550 2% 551 8% 552 twenty one% 553 39% 554 52% 555 73% 558 2% 559 17% 562 11% 564 66% 565 80% 566 89% 567 86% 571 17%

Test Example 17

Evaluation of transferin peptide derivatives for reducing blood testosterone levels using adult male rats

A peptide solution at a concentration of 1 mM was prepared by dissolving a transferin peptide derivative (hereinafter, referred to as peptide) in a 50% DMSO aqueous solution. The peptide solution was filled into 5 ALZET osmotic pumps (Model 2001, 0.2 ml volume, release rate 0.001 ml/hr, DUREECT Corporation). ALZET pumps filled with the peptide solution were implanted subcutaneously in the back of five CD(SD)IGS male 9-week-old rats (Charles RiverJapan, Inc.), one each, under ether anesthesia. In addition, as a negative control, 5 male CD(SD)IGS rats (Charles River Japan, Inc.) were implanted with ALZET osmotic pumps filled with distilled water. Rats were reared for 6 days under normal feeding conditions. After weighing, the animals were decapitated and blood samples were taken. After adding 0.03 ml of aprotinin solution (Trasylol, Bayer) containing 0.1 mg/ml EDTA.2Na per 1 ml of blood, the plasma was centrifuged at 1800×g for 25 minutes, and the plasma was recovered. Using 0.05 ml of the obtained plasma, the blood testosterone level of each rat was measured by radioimmunoassay (DPC. Total Testosterone Kit, Diagnostic Products Corporation). Values below the detection limit of the radioimmunoassay (plasma concentration 0.04 ng/ml) were scored as 0. The mean value of the testosterone level of the 5 rats administered with the peptide was calculated, and the relative value (percentage) of this mean value to the mean value (percentage) of the testosterone level of the 5 rats administered with distilled water was calculated. An example of the results of evaluation of various peptides by this evaluation method is shown in Table 31.

[Table 31]

Compound No.   Testosterone levels in the blood 305 2% 501 2% 545 2% 548 18% 555 2% 564 2% 589 2% 590 2% 591 2% 592 2% 595 3% 598 2% 599 2% 600 2% 602 2% 608 2% 612 2% 613 2% 615 2% 616 2% 617 2% 618 2% 621 2% 623 2% 625 2% 626 2% 627 2% 629 2% 630 2% 635 2% 637 2% 638 2% 642 2% 648 2% 649 2% 650 2% 651 2% 652 2% 657 2% 658 2% 660 2% 662 2% 663 2% 664 6% 666 2% 667 2% 670 2% 671 2% 672 2% 674 2% 675 2% 676 2% 677 2%

[sequence listing separate text]

SEQ ID NO: 15 The C-terminus is amidated

SEQ ID NO: 16 The C-terminus is amidated

SEQ ID NO: 17 The C-terminus is amidated

SEQ ID NO: 18 The C-terminus is amidated

Sequence Listing

<110>Takeda Pharmaceutical Company Limited

<120> Transferin derivatives and uses thereof

<130>G06-0070

<140>PCT/JP2005/012021

<141>2005-06-23

<150> JP 2004-187671

<151>2004-06-25

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<213> Human (Homo sapiens)

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Gly Thr Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln

1 5 10 15

Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly

20 25 30

Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn

35 40 45

Ser Phe Gly Leu Arg Phe

50

<210>2

<211>162

<212>DNA

<213> Human (Homo sapiens)

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gacctgccga actacaactg gaactctttc ggtctgcgtt tc 162

<210>3

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<213> mouse (Mus musculus)

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Met Tyr Leu Arg Phe Gly Val Asp Val Cys Ser Leu Ser Pro Trp Lys

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Glu Thr Val Asp Leu Pro Leu Pro Pro Arg Met Ile Ser Met Ala Ser

20 25 30

Trp Gln Leu Leu Leu Leu Leu Cys Val Ala Thr Tyr Gly Glu Pro Leu

35 40 45

Ala Lys Val Ala Pro Gly Ser Thr Gly Gln Gln Ser Gly Pro Gln Glu

50 55 60

Leu Val Asn Ala Trp Glu Lys Glu Ser Arg Tyr Ala Glu Ser Lys Pro

65 70 75 80

Gly Ser Ala Gly Leu Arg Ala Arg Arg Ser Ser Pro Cys Pro Pro Val

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Glu Gly Pro Ala Gly Arg Gln Arg Pro Leu Cys Ala Ser Arg Ser Arg

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Leu Ile Pro Ala Pro Arg Gly Ala Val Leu Val Gln Arg Glu Lys Asp

115 120 125

Leu Ser Thr Tyr Asn Trp Asn Ser Phe Gly Leu Arg Tyr Gly Arg Arg

130 135 140

Gln Ala Ala Arg Ala Ala Arg Gly

145 150

<210>4

<211>456

<212>DNA

<213> mouse (Mus musculus)

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atgtatctga gatttggcgt tgatgtctgc agcctgagtc cctggaagga gactgtagac 60

ctgccccttc ctccccagaat gatctcaatg gcttcttggc agctgctgct tctcctctgt 120

gtcgccacct atggggagcc gctggcaaaa gtgaagcctg gatccacagg ccagcagtcc 180

ggaccccagg aactcgttaa tgcctgggaa aaggaatcgc ggtatgcaga gagcaagcct 240

gggtctgcag ggctgcgcgc tcgtaggtcg tcgccatgcc cgccggttga gggccccgcg 300

gggcgccagc ggcccctgtg tgcctcccgc agtcgcctga tccctgcgcc ccgcggagcg 360

gtgctggtgc agcgggagaa ggacctgtcc acctacaact ggaactcctt cggcctgcgc 420

tacggcagga ggcaggcggc gcgggcagca cggggc 456

<210>5

<211>156

<212>PRT

<213> mouse (Mus musculus)

<400>5

Met Tyr Leu Arg Phe Gly Val Asp Val Cys Ser Leu Ser Pro Trp Lys

5 10 15

Glu Thr Val Asp Leu Pro Leu Pro Pro Arg Met Ile Ser Met Ala Ser

20 25 30

Trp Gln Leu Leu Leu Leu Leu Cys Val Ala Thr Tyr Gly Glu Pro Leu

35 40 45

Ala Lys Val Ala Pro Leu Val Lys Pro Gly Ser Thr Gly Gln Gln Ser

50 55 60

Gly Pro Gln Glu Leu Val Asn Ala Trp Glu Lys Glu Ser Arg Tyr Ala

65 70 75 80

Glu Ser Lys Pro Gly Ser Ala Gly Leu Arg Ala Arg Arg Ser Ser Pro

85 90 95

Cys Pro Pro Val Glu Gly Pro Ala Gly Arg Gln Arg Pro Leu Cys Ala

100 105 110

Ser Arg Ser Arg Leu Ile Pro Ala Pro Arg Gly Ala Val Leu Val Gln

115 120 125

Arg Glu Lys Asp Leu Ser Thr Tyr Asn Trp Asn Ser Phe Gly Leu Arg

130 135 140

Tyr Gly Arg Arg Gln Ala Ala Arg Ala Ala Arg Gly

145 150 155

<210>6

<211>468

<212>DNA

<213> mouse (Mus musculus)

<400>6

atgtatctga gatttggcgt tgatgtctgc agcctgagtc cctggaagga gactgtagac 60

ctgccccttc ctccccagaat gatctcaatg gcttcttggc agctgctgct tctcctctgt 120

gtcgccacct atggggagcc gctggcaaaa gtggcacctt tggtgaagcc tggatccaca 180

ggccagcagt ccggaccccca ggaactcgtt aatgcctggg aaaaggaatc gcggtatgca 240

gagagcaagc ctgggtctgc agggctgcgc gctcgtaggt cgtcgccatg cccgccggtt 300

gagggccccg cggggcgcca gcggcccctg tgtgcctccc gcagtcgcct gatccctgcg 360

ccccgcggag cggtgctggt gcagcggggag aaggacctgt ccacctacaa ctggaactcc 420

ttcggcctgc gctacggcag gaggcaggcg gcgcgggcag cacggggc 468

<210>7

<21l>130

<212>PRT

<213> Rat (Rattus sp.)

<400>7

Met Thr Ser Leu Ala Ser Trp Gln Leu Leu Leu Leu Leu Cys Val Ala

5 10 15

Ser Phe Gly Glu Pro Leu Ala Lys Met Ala Pro Val Val Asn Pro Glu

20 25 30

Pro Thr Gly Gln Gln Ser Gly Pro Gln Glu Leu Val Asn Ala Trp Gln

35 40 45

Lys Gly Pro Arg Tyr Ala Glu Ser Lys Pro Gly Ala Ala Gly Leu Arg

50 55 60

Ala Arg Arg Thr Ser Pro Cys Pro Pro Val Glu Asn Pro Thr Gly His

65 70 75 80

Gln Arg Pro Pro Cys Ala Thr Arg Ser Arg Leu Ile Pro Ala Pro Arg

85 90 95

Gly Ser Val Leu Val Gln Arg Glu Lys Asp Met Ser Ala Tyr Asn Trp

100 105 110

Asn Ser Phe Gly Leu Arg Tyr Gly Arg Arg Gln Val Ala Arg Ala Ala

115 120 125

Arg Gly

130

<210>8

<211>390

<212>DNA

<213> Rat (Rattus sp.)

<400>8

atgacctcgc tggcttcttg gcagctgctg cttctcctct gtgtggcctc ttttggggag 60

ccactggcaa aaatggcacc tgtggtgaac cctgaaccca caggccaaca gtccggaccc 120

caggaactcg ttaatgcctg gcaaaagggc ccgcggtatg cagagagcaa gcctggggct 180

gcaggactgc gcgctcgccg aacatcgcca tgcccgccgg tggagaaccc cacggggcac 240

cagcggcccc cgtgtgccac ccgcagtcgc ctgatccctg cgccccgcgg atcggtgctg 300

gtgcagcgcg agaaggacat gtcagcctac aactggaact cctttggcct gcgctacggc 360

aggaggcagg tggcgcgggc ggcacggggc 390

<210>9

<211>398

<212>PRT

<213> Human (Homo sapiens)

<400>9

Met His Thr Val Ala Thr Ser Gly Pro Asn Ala Ser Trp Gly Ala Pro

5 10 15

Ala Asn Ala Ser Gly Cys Pro Gly Cys Gly Ala Asn Ala Ser Asp Gly

20 25 30

Pro Val Pro Ser Pro Arg Ala Val Asp Ala Trp Leu Val Pro Leu Phe

35 40 45

Phe Ala Ala Leu Met Leu Leu Gly Leu Val Gly Asn Ser Leu Val Ile

50 55 60

Tyr Val Ile Cys Arg His Lys Pro Met Arg Thr Val Thr Asn Phe Tyr

65 70 75 80

Ile Ala Asn Leu Ala Ala Thr Asp Val Thr Phe Leu Leu Cys Cys Val

85 90 95

Pro Phe Thr Ala Leu Leu Tyr Pro Leu Pro Gly Trp Val Leu Gly Asp

100 105 110

Phe Met Cys Lys Phe Val Asn Tyr Ile Gln Gln Val Ser Val Gln Ala

115 120 125

Thr Cys Ala Thr Leu Thr Ala Met Ser Val Asp Arg Trp Tyr Val Thr

130 135 140

Val Phe Pro Leu Arg Ala Leu His Arg Arg Thr Pro Arg Leu Ala Leu

145 150 155 160

Ala Val Ser Leu Ser Ile Trp Val Gly Ser Ala Ala Val Ser Ala Pro

165 170 175

Val Leu Ala Leu His Arg Leu Ser Pro Gly Pro Arg Ala Tyr Cys Ser

180 185 190

Glu Ala Phe Pro Ser Arg Ala Leu Glu Arg Ala Phe Ala Leu Tyr Asn

195 200 205

Leu Leu Ala Leu Tyr Leu Leu Pro Leu Leu Ala Thr Cys Ala Cys Tyr

210 215 220

Ala Ala Met Leu Arg His Leu Gly Arg Val Ala Val Arg Pro Ala Pro

225 230 235 240

Ala Asp Ser Ala Leu Gln Gly Gln Val Leu Ala Glu Arg Ala Gly Ala

245 250 255

Val Arg Ala Lys Val Ser Arg Leu Val Ala Ala Val Val Leu Leu Phe

260 265 270

Ala Ala Cys Trp Gly Pro Ile Gln Leu Phe Leu Val Leu Gln Ala Leu

275 280 285

Gly Pro Ala Gly Ser Trp His Pro Arg Ser Tyr Ala Ala Tyr Ala Leu

290 295 300

Lys Thr Trp Ala His Cys Met Ser Tyr Ser Asn Ser Ala Leu Asn Pro

305 310 315 320

Leu Leu Tyr Ala Phe Leu Gly Ser His Phe Arg Gln Ala Phe Arg Arg

325 330 335

Val Cys Pro Cys Ala Pro Arg Arg Pro Arg Arg Pro Arg Arg Pro Gly

340 345 350

Pro Ser Asp Pro Ala Ala Pro His Ala Glu Leu His Arg Leu Gly Ser

355 360 365

His Pro Ala Pro Ala Arg Ala Gln Lys Pro Gly Ser Ser Gly Leu Ala

370 375 380

Ala Arg Gly Leu Cys Val Leu Gly Glu Asp Asn Ala Pro Leu

385 390 395

<210>10

<211>1194

<212>DNA

<213> Human (Homo sapiens)

<400>10

atgcacaccg tggctacgtc cggacccaac gcgtcctggg gggcaccggc caacgcctcc 60

ggctgcccgg gctgtggcgc caacgcctcg gacggcccag tcccttcgcc gcgggccgtg 120

gacgcctggc tcgtgccgct cttcttcgcg gcgctgatgc tgctgggcct ggtggggaac 180

tcgctggtca tctacgtcat ctgccgccac aagccgatgc ggaccgtgac caacttctac 240

atcgccaacc tggcggccac ggacgtgacc ttcctcctgt gctgcgtccc cttcacggcc 300

ctgctgtacc cgctgcccgg ctgggtgctg ggcgacttca tgtgcaagtt cgtcaactac 360

atccagcagg tctcggtgca ggccacgtgt gccactctga ccgccatgag tgtggaccgc 420

tggtacgtga cggtgttccc gttgcgcgcc ctgcaccgcc gcacgccccg cctggcgctg 480

gctgtcagcc tcagcatctg ggtaggctct gcggcggtgt ctgcgccggt gctcgccctg 540

caccgcctgt cacccgggcc gcgcgcctac tgcagtgagg ccttccccag ccgcgccctg 600

gagcgcgcct tcgcactgta caacctgctg gcgctgtacc tgctgccgct gctcgccacc 660

tgcgcctgct atgcggccat gctgcgccac ctgggccggg tcgccgtgcg ccccgcgccc 720

gccgatagcg ccctgcaggg gcaggtgctg gcagagcgcg caggcgccgt gcgggccaag 780

gtctcgcggc tggtggcggc cgtggtcctg ctcttcgccg cctgctgggg ccccatccag 840

ctgttcctgg tgctgcaggc gctgggcccc gcgggctcct ggcaccacg cagctacgcc 900

gcctacgcgc ttaagacctg ggctcactgc atgtcctaca gcaactccgc gctgaacccg 960

ctgctctacg ccttcctggg ctcgcacttc cgacaggcct tccgccgcgt ctgcccctgc 1020

gcgccgcgcc gcccccgccg cccccgccgg cccggaccct cggaccccgc agccccacac 1080

gcggagctgc accgcctggg gtcccacccg gcccccgcca gggcgcagaa gccagggagc 1140

agtgggctgg ccgcgcgcgg gctgtgcgtc ctgggggagg acaacgcccc tctc 1194

<210>11

<211>396

<212>PRT

<213> Rat (Rattus sp.)

<400>11

Met Ala Ala Glu Ala Thr Leu Gly Pro Asn Val Ser Trp Trp Ala Pro

5 10 15

Ser Asn Ala Ser Gly Cys Pro Gly Cys Gly Val Asn Ala Ser Asp Gly

20 25 30

Pro Gly Ser Ala Pro Arg Pro Leu Asp Ala Trp Leu Val Pro Leu Phe

35 40 45

Phe Ala Ala Leu Met Leu Leu Gly Leu Val Gly Asn Ser Leu Val Ile

50 55 60

Phe Val Ile Cys Arg His Lys His Met Gln Thr Val Thr Asn Phe Tyr

65 70 75 80

Ile Ala Asn Leu Ala Ala Thr Asp Val Thr Phe Leu Leu Cys Cys Val

85 90 95

Pro Phe Thr Ala Leu Leu Tyr Pro Leu Pro Thr Trp Val Leu Gly Asp

100 105 110

Phe Met Cys Lys Phe Val Asn Tyr Ile Gln Gln Val Ser Val Gln Ala

115 120 125

Thr Cys Ala Thr Leu Thr Ala Met Ser Val Asp Arg Trp Tyr Val Thr

130 135 140

Val Phe Pro Leu Arg Ala Leu His Arg Arg Thr Pro Arg Leu Ala Leu

145 150 155 160

Thr Val Ser Leu Ser Ile Trp Val Gly Ser Ala Ala Val Ser Ala Pro

165 170 175

Val Leu Ala Leu His Arg Leu Ser Pro Gly Pro His Thr Tyr Cys Ser

180 185 190

Glu Ala Phe Pro Ser Arg Ala Leu Glu Arg Ala Phe Ala Leu Tyr Asn

195 200 205

Leu Leu Ala Leu Tyr Leu Leu Pro Leu Leu Ala Thr Cys Ala Cys Tyr

210 215 220

Gly Ala Met Leu Arg His Leu Gly Arg Ala Ala Val Arg Pro Ala Pro

225 230 235 240

Thr Asp Gly Ala Leu Gln Gly Gln Leu Leu Ala Gln Arg Ala Gly Ala

245 250 255

Val Arg Thr Lys Val Ser Arg Leu Val Ala Ala Val Val Leu Leu Phe

260 265 270

Ala Ala Cys Trp Gly Pro Ile Gln Leu Phe Leu Val Leu Gln Ala Leu

275 280 285

Gly Pro Ser Gly Ala Trp His Pro Arg Ser Tyr Ala Ala Tyr Ala Leu

290 295 300

Lys Ile Trp Ala His Cys Met Ser Tyr Ser Asn Ser Ala Leu Asn Pro

305 310 315 320

Leu Leu Tyr Ala Phe Leu Gly Ser His Phe Arg Gln Ala Phe Cys Arg

325 330 335

Val Cys Pro Cys Gly Pro Gln Arg Gln Arg Arg Pro His Ala Ser Ala

340 345 350

His Ser Asp Arg Ala Ala Pro His Ser Val Pro His Ser Arg Ala Ala

355 360 365

His Pro Val Arg Val Arg Thr Pro Glu Pro Gly Asn Pro Val Val Arg

370 375 380

Ser Pro Ser Val Gln Asp Glu His Thr Ala Pro Leu

385 390 395

<210>12

<211>1188

<212>DNA

<213> Rat (Rattus sp.)

<400>12

atggccgcag aggcgacgtt gggtccgaac gtgagctggt gggctccgtc caacgcttcg 60

ggatgcccgg gctgcggtgt caatgcctcg gatggcccag gctccgcgcc aaggcccctg 120

gatgcctggc tggtgcccct gtttttcgct gccctaatgt tgctggggct agtcgggaac 180

tcactggtca tcttcgttat ctgccgccac aagcacatgc agaccgtcac caatttctac 240

atcgctaacc tggcggccac agatgtcact ttccttctgt gctgcgtacc cttcaccgcg 300

ctcctctatc cgctgcccac ctgggtgctg ggagacttca tgtgcaaatt cgtcaactac 360

atccagcagg tctcggtgca agccacatgt gccactttga cagccatgag tgtggaccgc 420

tggtacgtga ctgtgttccc gctgcgtgca cttcaccgcc gcactccgcg cctggccctg 480

actgtcagcc ttagcatctg ggtgggttcc gcagctgttt ccgccccggt gctggctctg 540

caccgcctgt cgcccgggcc tcacacctac tgcagtgagg cgtttcccag ccgtgccctg 600

gagcgcgctt tcgcgctcta caacctgctg gccctatacc tgctgccgct gctcgccacc 660

tgcgcctgct acggtgccat gctgcgccac ctgggccgcg ccgctgtacg ccccgcaccc 720

actgatggcg ccctgcaggg gcagctgcta gcacagcgcg ctggagcagt gcgcaccaag 780

gtctcccggc tggtggccgc tgtcgtcctg ctcttcgccg cctgctgggg cccgatccag 840

ctgttcctgg tgcttcaagc cctgggcccc tcgggggcct ggcaccctcg aagctatgcc 900

gcctacgcgc tcaagatctg ggctcactgc atgtcctaca gcaattctgc gctcaacccg 960

ctgctctatg ccttcctggg ttcccacttc agacaggcct tctgccgcgt gtgcccctgc 1020

ggcccgcaac gccagcgtcg gccccacgcg tcagcgcact cggaccgagc cgcaccccat 1080

agtgtgccgc acagccgggc tgcgcaccct gtccgggtca ggacccccga gcctgggaac 1140

cctgtggtgc gctcgccctc tgttcaggat gaacacactg ccccactc 1188

<210>13

<211>396

<212>PRT

<213> mouse (Mus musculus)

<400>13

Met Ala Thr Glu Ala Thr Leu Ala Pro Asn Val Thr Trp Trp Ala Pro

1 5 10 15

Ser Asn Ala Ser Gly Cys Pro Gly Cys Gly Val Asn Ala Ser Asp Asp

20 25 30

Pro Gly Ser Ala Pro Arg Pro Leu Asp Ala Trp Leu Val Pro Leu Phe

35 40 45

Phe Ala Thr Leu Met Leu Leu Gly Leu Val Gly Asn Ser Leu Val Ile

50 55 60

Tyr Val Ile Cys Arg His Lys His Met Gln Thr Val Thr Asn Phe Tyr

65 70 75 80

Ile Ala Asn Leu Ala Ala Thr Asp Val Thr Phe Leu Leu Cys Cys Val

85 90 95

Pro Phe Thr Ala Leu Leu Tyr Pro Leu Pro Ala Trp Val Leu Gly Asp

100 105 110

Phe Met Cys Lys Phe Val Asn Tyr Ile Gln Gln Val Ser Val Gln Ala

115 120 125

Thr Cys Ala Thr Leu Thr Ala Met Ser Val Asp Arg Trp Tyr Val Thr

130 135 140

Val Phe Pro Leu Arg Ala Leu His Arg Arg Thr Pro Arg Leu Ala Leu

145 150 155 160

Ala Val Ser Leu Ser Ile Trp Val Gly Ser Ala Ala Val Ser Ala Pro

165 170 175

Val Leu Ala Leu His Arg Leu Ser Pro Gly Pro Arg Thr Tyr Cys Ser

180 185 190

Glu Ala Phe Pro Ser Arg Ala Leu Glu Arg Ala Phe Ala Leu Tyr Asn

195 200 205

Leu Leu Ala Leu Tyr Leu Leu Pro Leu Leu Ala Thr Cys Ala Cys Tyr

210 215 220

Gly Ala Met Leu Arg His Leu Gly Arg Ala Ala Val Arg Pro Ala Pro

225 230 235 240

Thr Asp Gly Ala Leu Gln Gly Gln Leu Leu Ala Gln Arg Ala Gly Ala

245 250 255

Val Arg Thr Lys Val Ser Arg Leu Val Ala Ala Val Val Leu Leu Phe

260 265 270

Ala Ala Cys Trp Gly Pro Ile Gln Leu Phe Leu Val Leu Gln Ala Leu

275 280 285

Gly Pro Ser Gly Ala Trp His Pro Arg Ser Tyr Ala Ala Tyr Ala Val

290 295 300

Lys Ile Trp Ala His Cys Met Ser Tyr Ser Asn Ser Ala Leu Asn Pro

305 310 315 320

Leu Leu Tyr Ala Phe Leu Gly Ser His Phe Arg Gln Ala Phe Cys Arg

325 330 335

Val Cys Pro Cys Cys Arg Gln Arg Gln Arg Arg Pro His Thr Ser Ala

340 345 350

His Ser Asp Arg Ala Ala Thr His Thr Val Pro His Ser Arg Ala Ala

355 360 365

His Pro Val Arg Ile Arg Ser Pro Glu Pro Gly Asn Pro Val Val Arg

370 375 380

Ser Pro Cys Ala Gln Ser Glu Arg Thr Ala Ser Leu

385 390 395

<210>14

<211>1188

<212>DNA

<213> mouse (Mus musculus)

<400>14

atggccaccg aggcgacatt ggctcccaat gtgacctggt gggctccgtc caacgcttca 60

ggatgcccag gctgcggtgt caacgcctcg gatgacccag gctctgcgcc aaggcccctg 120

gatgcctggc tggttcccct gtttttcgct acactcatgt tgcttgggct ggtcggaaac 180

tcattggtca tctacgttat ctgccgccac aagcacatgc agacagttac caacttctac 240

atcgctaacc tggctgccac agacgtcact ttccctactgt gctgcgtgcc cttcaccgca 300

ctcctctacc cgctgcccgc ctgggtgctg ggagacttca tgtgcaaatt cgtcaactac 360

atccagcagg tctcggtgca agccacatgt gccactctga cggccatgag tgtggaccgc 420

tggtatgtga ctgtgttccc gctgcgtgca cttcaccgcc gcactccgcg cctggccctg 480

gctgtcagcc tcagcatctg ggtggggtca gcagetgtgt ccgccccggt gctggccctg 540

caccgcctgt cgccagggcc tcgcacctac tgcagcgagg cgtttcccag ccgcgccctg 600

gagcgcgcct tcgcgctcta caacctgctg gctctatatc tgctgccgct gctcgccacc 660

tgcgcctgct acggcgccat gctgcgccac ctgggccgtg cggctgtacg ccccgcaccc 720

actgacggcg ccctgcaggg acagctgcta gcacagcgcg ccggagcagt gcgcaccaag 780

gtctcccggc tggtggccgc tgtcgtcctg ctcttcgccg cctgctgggg cccgatccag 840

ctgttcctgg tgcttcaagc cctgggcccc tcgggggcct ggcaccctcg aagctatgcc 900

gcctacgcgg tcaagatctg ggctcactgc atgtcctaca gcaactcggc gctcaatccg 960

ctgctctatg ccttcctggg ttcacacttc agacaggcct tctgccgcgt gtgcccctgc 1020

tgccggcaac gccagcgccg gccccaacacg tcagcgcact cggaccgagc tgcaactcac 1080

actgtgccgc acagccgtgc tgcgcaccct gtgcggatca ggagcccgga gcctgggaac 1140

cctgtggtgc gctcgccctg cgctcagagt gaacgcactg cctcactc 1188

<210>15

<211>15

<212>PRT

<213> Artificial

<220>

<223> The C-terminus of the polypeptide is in the form of an amide (-CONH2)

<400>15

Lys Asp Leu Pro Asn Tyr Asn Trp Asn Ser Phe Gly Leu Arg Phe

1 5 10 15

<210>16

<211>10

<212>PRT

<213> Artificial

<220>

<223> The C-terminus of the polypeptide is in the form of an amide (-CONH2)

<400>16

Tyr Asn Trp Asn Ser Phe Gly Leu Arg Phe

1 5 10

<210>17

<211>9

<212>PRT

<213> Artificial

<220>

<223> The C-terminus of the polypeptide is in the form of an amide (-CONH2)

<400>17

Asn Trp Asn Ser Phe Gly Leu Arg Phe

1 5 9

<210>18

<211>8

<212>PRT

<213> Artificial

<220>

<223> The C-terminus of the polypeptide is in the form of an amide (-CONH2)

<400>18

Trp Asn Ser Phe Gly Leu Arg Phe

1 5 8

<210>19

<211>45

<212>DNA

<213> Human (Homo sapiens)

<400>19

aaggacctgc cgaactacaa ctggaactcc ttcggcctgc gcttc 45

<210>20

<211>30

<212>DNA

<213> Human (Homo sapiens)

<400>20

tacaactgga actccttcgg cctgcgcttc 30

<210>21

<211>27

<212>DNA

<213> Human (Homo sapiens)

<400>21

aactggaact ccttcggcct gcgcttc 27

<210>22

<211>24

<212>DNA

<213> Human (Homo sapiens)

<400>22

tggaactcct tcggcctgcg cttc 24

Claims (55)

1. A transferin derivative (II) represented by the following formula, or a salt thereof, Wherein, V represents the group shown in the following formula: Or a group represented by the following formula: n means 0 or 1; W ¹ represents N, CH or O (provided that when W ¹ is N or CH, n represents 1, and when W ¹ is O, n represents 0); W ² represents N or CH; Z ¹ , Z ³ , Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group; Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S; ^R represents (1) a hydrogen atom, or (2) a cyclic or chain C _1-10 alkyl group, or (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a chain alkyl group, or ( 4) C _1-8 alkyl, said C _1-8 alkyl is optionally substituted by a substituent selected from an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic ring group; ^R represents (1) C _1-8 alkyl, said C _1-8 alkyl has an optionally substituted basic group and optionally has other substituents, (2) aralkyl, said aralkyl An optionally substituted basic group and optionally other substituents, (3) C _1-4 alkyl, the C _1-4 alkyl having a non-aromatic ring hydrocarbon group with no more than 7 carbon atoms and any Optionally have other substituents, the non-aromatic cyclic hydrocarbon group has an optionally substituted basic group, or (4) C _1-4 alkyl, the C _1-4 alkyl has no more than 7 carbon atoms A non-aromatic heterocyclic group and optionally other substituents, the non-aromatic heterocyclic group has an optionally substituted basic group; R ⁴ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally Substituted C _8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms , the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms Aromatic heterocyclic group; Q ¹ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally Substituted C _8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms , the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms Aromatic heterocyclic group; Q ² represents (1) CH ₂ , which may _{be optionally substituted by optionally substituted C 1-4 alkyl} having a substituent selected from carbamoyl _and hydroxyl, ( 2) NH, which _may be optionally substituted by optionally substituted C _1-4 alkyl having a substituent selected from carbamoyl and hydroxyl, or (3) O; Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO- or -CH ₂ CH ₂ -, which may be optionally substituted by C _1-6 alkyl; and, Z ⁹ represents a hydrogen atom, O or S; and, P and P' can be the same or different, and each can be combined to form a ring by P and P', or P and ^Q1 , and represent: (1) Hydrogen atom; (2) Optional amino acid residues that are continuously or discontinuously combined with the C-terminus of the 1-48 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1; (3) A group represented by the following formula: J ¹ -J ² -C(J ³ )(Q ³ )Y ¹ C(J ⁴ )(Q ⁴ )Y ² C(J ⁵ )(Q ⁵ )Y ³ C(J ⁶ )(Q ⁶ )C( =Z ¹⁰ )- (in, ^J represents (a) a hydrogen atom, or (b) (i) C _1-15 acyl, (ii) C _1-15 alkyl, (iii) C _6-14 aryl, (iv) carbamoyl, ( v) carboxy, (vi) sulfinate, (vii) amidino, (viii) glyoxyl or (ix) amino, these groups may be optionally substituted with substituents containing optionally substituted cyclic groups; J ² represents (1) NH optionally substituted by C _1-6 alkyl, (2) CH ₂ optionally substituted by C _1-6 alkyl, (3) O, or (4) S; Each of J ³ to J ⁶ represents a hydrogen atom or a C _1-3 alkyl group; Q ³ to Q ⁶ each represent a C _1-4 alkyl group or a hydrogen atom, and the C _1-4 alkyl group optionally has a substituent selected from the following: (1) Optionally substituted C _6-12 aromatic hydrocarbon groups, (2) An optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atoms, (3) Optionally substituted C _8-14 aromatic condensed ring groups, (4) An optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atom, (5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, (6) An optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms, (7) Optionally substituted amino groups, (8) Optionally substituted guanidino, (9) optionally substituted hydroxyl, (10) Optionally substituted carboxy, (11) optionally substituted carbamoyl, and (12) optionally substituted mercapto; J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ can be combined together, or J ² and Q ³ , Y ¹ and Q 4 , Y ² and Q ⁵ or Y ^{3 and} Q ⁶ can be combined to form a ring; Each of ^Y1 to ^Y3 represents a group shown below: -CON(J ¹³ )-, -CSN(J ¹³ )-, -C(J ¹⁴ )N(J ¹³ )-or -N(J ¹³ )CO- (wherein J ¹³ and J ¹⁴ each represent a hydrogen atom or C _1-3 alkyl); and Z ¹⁰ represents a hydrogen atom, O or S); (4) A group represented by the following formula: J ¹ -J ² -C(J ⁷ )(Q ⁷ )Y ² C(J ⁸ )(Q ⁸ )Y ³ C(J ⁹ )(Q ⁹ )C(=Z ¹⁰ )- (in: ^J1 and ^J2 each have the same meaning as above; J ⁷ to J ⁹ have the same meaning as J ³ ; Q ⁷ to Q ⁹ have the same meaning as Q ³ ; ^Y2 and ^Y3 each have the same meaning as above; Z ¹⁰ has the same meaning as above; J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ can be combined together, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ can be combined together to form a ring); (5) A group represented by the following formula: J ¹ -J ² -C(J ¹⁰ )(Q ¹⁰ )Y ³ C(J ¹¹ )(Q ¹¹ )C(=Z ¹⁰ )- (in: J ¹ and J ² have the same meaning as above; J ¹⁰ and J ¹¹ have the same meaning as J ³ ; Q ¹⁰ and Q ¹¹ have the same meaning as Q ³ ; ^Y3 has the same meaning as above; Z ¹⁰ has the same meaning as above; J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ can be combined together, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ can be combined to form a ring); (6) A group represented by the following formula: J ¹ -J ² -C(J ¹² )(Q ¹² )C(=Z ¹⁰ )- (in: J ¹ and J ² have the same meaning as above; J ¹² has the same meaning as J ³ ; Q ¹² has the same meaning as Q ³ ; Z ¹⁰ has the same meaning as above; J ¹² and Q ¹² may be combined together, or J ² and Q ¹² may be combined to form a ring); or, (7) A group represented by the following formula: J ¹ - (in: J ¹ has the same meaning as above) (the condition is that the sequence consisting of 1-54, 2-54, 3-54, 4-54, 5-54, 6-54, 7 in the amino acid sequence shown in SEQ ID NO: 1 is not included -54, 8-54, 9-54, 10-54, 11-54, 12-54, 13-54, 14-54, 15-54, 16-54, 17-54, 18-54, 19-54 , 20-54, 21-54, 22-54, 23-54, 24-54, 25-54, 26-54, 27-54, 28-54, 29-54, 30-54, 31-54, 32 -54, 33-54, 34-54, 35-54, 36-54, 37-54, 38-54, 39-54, 40-54, 41-54, 42-54, 43-54, 44-54 , 45-54, 46-54, 47-54, 48-54 or 49-54 amino acid sequence). 2. transferin derivative (II) or its salt according to claim 1, wherein, V is a group shown in the following formula: (Wherein, the meaning of each symbol is the same as the definition in claim 1). 3. transferin derivative (II) or its salt according to claim 1, wherein, V is a group shown in the following formula: (Wherein, the meaning of each symbol is the same as the definition in claim 1). 4. A prodrug of the transferin derivative (II) or a salt thereof according to claim 1. 5. A pharmaceutical composition comprising the transferin derivative (II) or a salt thereof according to claim 1, or a prodrug thereof. 6. The pharmaceutical composition according to claim 5, which is a drug for suppressing cancer metastasis or a drug for suppressing cancer growth. 7. The pharmaceutical composition according to claim 5, which is a drug for preventing or treating cancer. 8. The pharmaceutical composition according to claim 5, which is a drug for controlling placental function. 9. The pharmaceutical composition according to claim 5, which is a drug for preventing or treating choriocarcinoma, hydatidiform mole, invasive hydatidiform mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism, and labor induction . 10. The pharmaceutical composition according to claim 5, which is a drug for improving gonadal function. 11. The pharmaceutical composition according to claim 5, which is a drug for preventing or treating hormone-dependent cancer, infertility, endometriosis, premature puberty or uterine fibroids. 12. The pharmaceutical composition according to claim 5, which is a drug for inducing or stimulating ovulation. 13. The pharmaceutical composition according to claim 5, which is a gonadotropin secretagogue or a sex hormone secretagogue. 14. The pharmaceutical composition according to claim 5, which is a drug for preventing or treating Alzheimer's disease or mild cognitive impairment. 15. A method for inhibiting cancer metastasis or cancer growth, which comprises administering an effective dose of the transferin derivative (II) or salt thereof according to claim 1, or a prodrug thereof, to a mammal. 16. A method for preventing or treating cancer, the method comprising administering an effective dose of the transferin derivative (II) or salt thereof according to claim 1 to mammals, or their prodrugs 17. A method for controlling placental function, which comprises administering an effective dose of the transferin derivative (II) or a salt thereof according to claim 1, or a prodrug thereof, to a mammal. 18. A method for preventing or treating choriocarcinoma, hydatidiform mole, invasive hydatidiform mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction, the method comprising administering an effective dose of the compound of claim 1 to mammals The aforementioned transferin derivatives (II) or salts thereof, or their prodrugs. 19. A method for improving gonadal function, which comprises administering an effective dose of the transferin derivative (II) or salt thereof according to claim 1, or a prodrug thereof, to a mammal. 20. A method for preventing or treating hormone-dependent cancer, infertility, endometriosis, premature puberty or uterine fibroids, the method comprising administering an effective dose of the transferin derivative (II ) or salts thereof, or their prodrugs. 21. A method for inducing or stimulating ovulation, the method comprising administering an effective dose of the transferin derivative (II) or salt thereof according to claim 1 to mammals, or their prodrugs 22. A method for promoting gonadotropin secretion or sex hormone secretion, the method comprising administering an effective dose of the transferin derivative (II) or salt thereof according to claim 1, or a prodrug thereof, to a mammal. 23. A method for preventing or treating Alzheimer's disease or mild cognitive impairment, the method comprising administering to a mammal an effective dose of the transferin derivative (II) or a salt thereof according to claim 1, or their prodrug. 24. Use of the transferin derivative (II) or salt thereof as claimed in claim 1, or their prodrugs in the preparation of drugs for inhibiting cancer metastasis or cancer growth. 25. Use of the transferin derivative (II) or salt thereof as claimed in claim 1, or a prodrug thereof, in the preparation of a medicament for preventing or treating cancer. 26. Use of the transferin derivative (II) or salt thereof as claimed in claim 1, or a prodrug thereof, in the preparation of a medicament for controlling placental function. 27. The transferin derivative (II) or its salt according to claim 1, or their prodrugs are used in the preparation for the prevention or treatment of choriocarcinoma, hydatidiform mole, invasive hydatidiform mole, miscarriage, fetal hypoplasia, glucose Use in preparations for metabolic abnormalities, dyslipidemia or labor induction. 28. Use of the transferin derivative (II) or salt thereof as claimed in claim 1, or their prodrugs in the preparation of medicaments for improving gonadal function. 29. The transferin derivative (II) or salt thereof according to claim 1, or their prodrugs are used in the preparation for the prevention or treatment of hormone-dependent cancer, infertility, endometriosis, premature puberty or uterine muscle The use in the medicine of tumor. 30. Use of the transferin derivative (II) or salt thereof as claimed in claim 1, or their prodrugs in the preparation of medicaments for inducing or stimulating ovulation. 31. Use of the transferin derivative (II) or salt thereof as claimed in claim 1, or their prodrugs in the preparation of gonadotropin secretagogues or sex hormone secretagogues. 32. Use of the transferin derivative (II) or its salt according to claim 1, or their prodrugs in the preparation of medicaments for preventing or treating Alzheimer's disease or mild cognitive impairment. 33. A drug for inhibiting the secretion of gonadotropins or a drug for inhibiting the secretion of sex hormones, comprising a transferin derivative (III) or a salt thereof represented by the following formula, or a prodrug thereof,

[in: V' represents a group shown in the following formula: A group represented by the following formula:

Or a group represented by the following formula:

n means 0 or 1; W ¹ represents N, CH or O (provided that when W ¹ is N or CH, n represents 1, and when W ¹ is O, n represents 0); W ² represents N or CH; Z ¹ , Z ³ , Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group; Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S; ^R represents (1) a hydrogen atom, (2) a C _1-8 alkyl group, and the C _1-8 alkyl group is optionally selected from optionally substituted carbamoyl, optionally substituted hydroxyl and optionally The substituent of the substituted aromatic ring group is substituted, (3) cyclic or chain C _1-10 alkyl, or (4) C _1-10 alkyl consisting of cycloalkyl and chain alkyl, or ( 5) optionally substituted aromatic ring groups; R ² represents (1) hydrogen atom, or (2) cyclic or chain C _1-10 alkyl, (3) C _1-10 alkyl consisting of cycloalkyl and chain alkyl, or (4) C _1-8 alkyl, the C _1-8 alkyl is optionally substituted by a substituent selected from an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic ring group; ^R represents (1) C _1-8 alkyl, said C _1-8 alkyl has an optionally substituted basic group and optionally has other substituents, (2) aralkyl, said aralkyl An optionally substituted basic group and optionally other substituents, (3) C _1-4 alkyl, the C _1-4 alkyl having a non-aromatic ring hydrocarbon group with no more than 7 carbon atoms and any Optionally have other substituents, the non-aromatic cyclic hydrocarbon group has an optionally substituted basic group, or (4) C _1-4 alkyl, the C _1-4 alkyl has no more than 7 carbon atoms A non-aromatic heterocyclic group and optionally other substituents, the non-aromatic heterocyclic group has an optionally substituted basic group; R ⁴ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally Substituted C _8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, the aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms, so The heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms Heterocyclyl; Q ¹ represents a C _1-4 alkyl group, and the C _1-4 alkyl group may be optionally substituted by a substituent selected from the following: (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally A substituted 5- to 14-membered aromatic heterocyclic group, the aromatic heterocyclic group is composed of 1-7 carbon atoms and heteroatoms, the heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (3) optionally substituted C _8-14 aromatic condensed ring group, (4) optionally substituted 5 to 14 membered aromatic fused heterocyclic group, said aromatic fused heterocyclic group is composed of 3-11 carbon atoms and heteroatoms, said Heteroatoms are selected from nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, and (6) optionally substituted non-aromatic heterohydrocarbon groups with no more than 7 carbon atoms ring group; Q ² represents (1) CH ₂ , which may _{be optionally substituted by optionally substituted C 1-4 alkyl} having a substituent selected from carbamoyl _and hydroxyl, ( ₂ ) NH, which may be optionally substituted by optionally substituted C _1-4 alkyl having a substituent selected from carbamoyl and hydroxyl, or (3) O; Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH ₂ - or -CH=CH-, which may be optionally substituted by C _1-6 alkyl; and, Z ⁹ represents a hydrogen atom, O or S; and, P and P' can be the same or different, each can form a ring together through the combination of P and P' or P and ^Q1 , and represent: (1) Hydrogen atom; (2) Optional amino acid residues that are continuously or discontinuously combined with the C-terminus of the 1-48 amino acid sequence in the amino acid sequence shown in SEQ ID NO: 1; (3) A group represented by the following formula: J ¹ -J ² -C(J ³ )(Q ³ )Y ¹ C(J ⁴ )(Q ⁴ )Y ² C(J ⁵ )(Q ⁵ )Y ³ C(J ⁶ )(Q ⁶ )C( =Z ¹⁰ )- (in, ^J represents (a) a hydrogen atom, or (b) (i) C ^1-15 acyl, (ii) C ^1-15 alkyl, (iii) C ^6-14 aryl, (iv) carbamoyl, ( v) carboxy, (vi) sulfinate, (vii) amidino, (viii) glyoxyl or (ix) amino, these groups may be optionally substituted with substituents containing optionally substituted cyclic groups; J ² represents (1) NH optionally substituted by C _1-6 alkyl, (2) CH ₂ optionally substituted by C _1-6 alkyl, (3) O or (4) S; Each of J ³ to J ⁶ represents a hydrogen atom or a C _1-3 alkyl group; Q ³ to Q ⁶ each represent a C _1-4 alkyl group or a hydrogen atom, and the C _1-4 alkyl group optionally has a substituent selected from the following: (1) Optionally substituted C _6-12 aromatic hydrocarbon groups, (2) An optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a heteroatom selected from nitrogen, oxygen and sulfur atoms, (3) Optionally substituted C _8-14 aromatic condensed ring groups, (4) An optionally substituted 5- to 14-membered aromatic condensed heterocyclic group consisting of 3 to 11 carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur atoms, (5) Optionally substituted non-aromatic cyclic hydrocarbon groups with no more than 7 carbon atoms, (6) An optionally substituted non-aromatic heterocyclic group with no more than 7 carbon atoms, (7) Optionally substituted amino groups, (8) Optionally substituted guanidino, (9) optionally substituted hydroxyl, (10) Optionally substituted carboxy, (11) optionally substituted carbamoyl, and (12) optionally substituted mercapto; J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ can be combined together, or Z ¹ and R ¹ , J ² and Q ³ , Y ¹ and Q ⁴ , Y ² and Q ⁵ or Y ³ and Q ⁶ can be combined to form a ring; Y ¹ to Y ³ each represent a group described in the following formula: -CON(J ¹³ )-, -CSN(J ¹³ )-, -C(J ¹⁴ )N(J ¹³ )- or -N(J ¹³ )CO- (wherein J ¹³ and J ¹⁴ each represent a hydrogen atom or C _1-3 alkyl); and Z ¹⁰ represents a hydrogen atom, O or S); (4) A group represented by the following formula: J ¹ -J ² -C(J ⁷ )(Q ⁷ )Y ² C(J ⁸ )(Q ⁸ )Y ³ C(J ⁹ )(Q ⁹ )C(=Z ¹⁰ )- (in: ^J1 and ^J2 each have the same meaning as above; J ⁷ to J ⁹ have the same meaning as J ³ ; Q ⁷ to Q ⁹ have the same meaning as Q ³ ; ^Y2 and ^Y3 each have the same meaning as above; Z ¹⁰ has the same meaning as above; J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ can be combined together, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ can be combined to form a ring); (5) A group represented by the following formula: J ¹ -J ² -C(J ¹⁰ )(Q ¹⁰ )Y ³ C(J ¹¹ )(Q ¹¹ )C(=Z ¹⁰ )- (in: J ¹ and J ² have the same meaning as above; J ¹⁰ and J ¹¹ have the same meaning as J ³ ; Q ¹⁰ and Q ¹¹ have the same meaning as Q ³ ; ^Y3 has the same meaning as above; Z ¹⁰ has the same meaning as above; J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ can be combined together, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ can be combined to form a ring); (6) A group represented by the following formula: J ¹ -J ² -C(J ¹² )(Q ¹² )C(=Z ¹⁰ )- (in; J ¹ and J ² have the same meaning as above; J ¹² has the same meaning as J ³ ; Q ¹² has the same meaning as Q ³ ; Z ¹⁰ has the same meaning as above; J ¹² and Q ¹² may be combined together, or J ² and Q ¹² may be combined to form a ring); or, (7) A group represented by the following formula: J ¹ - (wherein, J ¹ has the same meaning as above)]. 34. The medicament according to claim 33, wherein the transferin derivative (III) is the transferin derivative (II) of claim 1. 35. The medicine according to claim 33, wherein V' is a group represented by the following formula: (wherein each symbol has the same meaning as described in claim 33). 36. The medicine according to claim 33, wherein, V' is a group represented by the following formula: (wherein each symbol has the same meaning as described in claim 33). 37. The medicine according to claim 33, V' is a group represented by the following formula:

(wherein each symbol has the same meaning as described in claim 33). 38. The drug according to claims 33-37, which is a down-regulator of gonadotropins or sex hormones. 39. The medicine according to claims 33 to 37, which is a down-regulator of human OT7T175 (transferase receptor) protein consisting of the amino acid sequence shown in SEQ ID NO:9. 40. The medicament according to claims 33 to 39, which is a medicament for preventing or treating hormone-dependent cancer. 41. A method for inhibiting gonadotropin secretion or sex hormone secretion, which comprises administering an effective dose of the transferin derivative (III) or salt thereof according to claim 33, or a prodrug thereof, to a mammal. 42. A method for down-regulating gonadotropins or sex hormones, the method comprising administering an effective dose of the transferin derivative or salt thereof according to claim 33, or a prodrug thereof, to a mammal. 43. A method for down-regulating the human OT7T175 (transferin receptor) protein composed of the amino acid sequence shown in SEQ ID NO: 9, the method comprising administering an effective dose of the transferin derivative or the transferin derivative described in claim 33 to a mammal salts, or their prodrugs. 44. A method for preventing or treating hormone-dependent cancer, which comprises administering an effective dose of the transferin derivative or salt thereof according to claim 33, or a prodrug thereof, to a mammal. 45. Use of the transferin derivatives or salts thereof as claimed in claim 33, or their prodrugs in the preparation of drugs for inhibiting gonadotropin secretion or drugs for inhibiting sex hormone secretion. 46. Use of the transferin derivatives or salts thereof as claimed in claim 33, or their prodrugs in the preparation of down-regulators for gonadotropins or sex hormones. 47. The transferin derivatives or salts thereof according to claim 33, or their prodrugs are used in the preparation of down-regulators for human OT7T175 (transferin receptor) protein composed of the amino acid sequence shown in SEQ ID NO: 9 the use of. 48. Use of the transferin derivatives or salts thereof as claimed in claim 33, or their prodrugs in the preparation of medicaments for the prevention or treatment of hormone-dependent cancers. 49. A transferin derivative represented by the following formula or a salt thereof: XX0-XX2-XX3-XX4-XX5-XX6-AzaGly-XX8-XX9-XX10-NH ₂ (in: XX0 represents formyl, C _1-6 alkanoyl, cyclopropanecarbonyl, 6-(acetyl-D-arginylamino) hexanoyl, 6-((R)-2,3-diaminopropionylamino) hexyl Acyl, 6-(D-norleucylamino)hexanoyl, 4-(D-arginylamino)butyryl, 3-(4-hydroxyphenyl)propionyl, glycyl, tyrosyl, acetyl Glycyl, acetyltyrosyl, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3-(pyridin-3-yl)propionyl, adipyl or 6-amino Hexanoyl; XX2 represents Tyr, D-Tyr, D-Ala, D-Leu, D-Phe, D-Lys, D-Trp or key arm; XX3 represents Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D-3-pyridylalanine or D-4-pyridylalanine; XX4 represents Asn, 2-amino-3-ureidopropionic acid, N ^β -formyl diaminopropionic acid or N ^β -acetyl diaminopropionic acid; XX5 means Ser, Thr or Val; XX6 represents Phe, Tyr, Trp, Tyr(Me), Thi, Nal(2), Cha, 4-pyridylalanine or 4-fluorophenylalanine; AzaGly means azaglycine; XX8 means Leu, Nva or Val; XX9 represents Arg, Orn, Arg(Me) or Arg(symMe2); XX10 represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine. 50. D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (compound number 305), D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 385), D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 501), Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 509), D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 512), Ac-D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 516), D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 540), D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 541), Benzoyl-Asn-Ser-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 545), D-Tyr-D-Pya(4)-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-PheΨ(CSNH)NH ₂ (Compound No. 548), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 550), Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 551), D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 552), D-Nle-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 553), D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 555), Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 558), 3-(4-hydroxyphenyl)propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 559), Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 562), Ac-D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 564), Cyclopropanecarbonyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 566), Butyryl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 567), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 571), Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 579), Ac-D-Tyr-D-Trp-Asn-Ser(Me)-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 580), Ac-D-Tyr-D-Trp-Dap(Ac)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 584), Ac-D-Tyr-D-Trp-Dap(For)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 585), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂ (Compound No. 589), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Thi-NH ₂ (Compound No. 590), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Tyr-NH ₂ (Compound No. 591), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂ (Compound No. 592), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Orn-Trp-NH ₂ (Compound No. 599), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂ (Compound No. 600), Ac-D-NMeTyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp- _NH2 (Compound No. 602), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(symMe2)-Trp-NH ₂ (Compound No. 608), For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 612), Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 613), Ac-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 615), Ac-D-Ala-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 616), Ac-D-Leu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 617), Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 618), Ac-D-Lys-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 621), Ac-D-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 623), Ac-D-Tyr-D-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 625), Ac-D-Tyr-D-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 626), Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 627), Ac-D-Tyr-D-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 629), Ac-D-Tyr-D-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 630), Ac-D-Tyr-D-Trp-Asn-Thr-Pya(4)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 635), Ac-D-Tyr-D-Trp-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 637), Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 638), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Val-Arg(Me)-Trp-NH ₂ (Compound No. 642), Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 648), Ac-Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 649), D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp- _NH2 (Compound No. 650), Ac-D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 651), pGlu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp- _NH2 (Compound No. 652), Ac-D-Tyr-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 657), Ac-D-Tyr-D-Pya(2)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 658), Ac-D-Tyr-D-Pya(3)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 660), Ac-D-Tyr-Tic-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 662), Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 663), Ac-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 666), Hexanoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 667), 3-pyridinepropionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 670), Adipyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 671), Ac-D-Tyr-NMeTrp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 672), 6-aminocaproyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 674), or a salt thereof. 51. Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (compound number 550), Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 551), D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 552), Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 558), 3-(4-hydroxyphenyl)propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 559), Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 562), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe-NH ₂ (Compound No. 571), Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 579), Ac-D-Tyr-D-Trp-Dap(For)-Ser-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 585), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Nal(2)-NH ₂ (Compound No. 589), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Phe(4F)-NH ₂ (Compound No. 592), For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 612), Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 613), Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 618), Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 627), Ac-D-Tyr-D-Trp-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 637), Ac-D-Tyr-D-Pya(4)-Asn-Thr-Phe(4F)-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 638), Ac-D-Tyr-D-Pya(2)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 658), Ac-D-Tyr-D-Pya(3)-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 660), Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH ₂ (Compound No. 663), or a salt thereof. 52. A method for improving stability in blood, the method comprising introducing one or two alkyl groups into the side chain of Arg of an Arg-containing peptide. 53. A method for improving stability in blood, comprising introducing one alkyl group into the side chain of Arg of an Arg-containing peptide. 54. A method of increasing stability in blood, the method comprising converting the side chain of Arg in an Arg-containing peptide to ^Nω -alkylated Arg. 55. The method of claims 52-54, wherein the alkyl group is a C _1-4 alkyl group. 56. The method of claims 52-54, wherein the alkyl group is methyl. 57. The method of claims 52-54, wherein the Arg-containing peptide is a peptide comprising a peptide fragment characterized by the structure of the formula, -Arg-XXX-, wherein XXX represents an amino acid having an optionally substituted aromatic ring group in the side chain. 58. The method of claim 57, wherein XXX is Phe, Trp or Tyr.

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